We characterized abnormalities of carbohydrate and lipid metabolism and determined whether those metabolic abnormalities are associated with extremity lesions in California mice (Peromyscus californicus).Blood samples were evaluated for glucose, cholesterol, triglyceride, and insulin concentrations. Necropsy and histologic evaluation were done on selected mice, including staining pancreatic sections for insulin. Physical examinations also were performed.California mice were found to have Type 2 diabetes mellitus (T2DM). Sections of pancreas from diabetic and prediabetic mice had pathologic changes consistent with T2DM. After six months of feeding a low-fat diet, mice were normoglycemic, normotriglyceridemic, and normocholesterolemic. Some mice remained hyperinsulinemic. Traumatic lesions were not associated with T2DM.California mice develop diet-related T2DM when fed a diet containing 25.8% kcal from fat. California mice may be a useful animal model of human T2DM, and traumatic lesions result from housing California mice in multiple male groups.
Liposome encapsulation of opioids by using an ammonium-sulfate-gradient loading technique significantly slows the release time of the drug. This study evaluated the duration of analgesia in a rodent model of monoarthritis after epidural administration of liposome-encapsulated hydromorphone (LE-hydromorphone; prepared by ammonium-sulfate-gradient loading) compared with standard hydromorphone and a negative control of blank liposomes. Analgesia was assessed by changes in thermal withdrawal latency, relative weight-bearing, and subjective behavioral scoring. Analgesia in arthritic rats was short-lived after epidural hydromorphone; increases in pain threshold were observed only at 2 h after administration. In contrast, thermal pain thresholds after epidural LE-hydromorphone were increased for as long as 72 h, and subjective lameness scores were lower for as long as 96 h after epidural administration. Injection of LE-hydromorphone epidurally was associated with various mild changes in CNS behavior, and 2 rats succumbed to respiratory depression and death. In conclusion, LE-hydromorphone prolonged the duration of epidural analgesia compared with the standard formulation of hydromorphone, but CNS side effects warrant careful administration of this LE-hydromorphone in future studies.
PURPOSE: Modern prosthetic limbs have reaped the benefits of the Digital Age, with improvements in materials, degrees of freedom and computational power. What has lagged behind these advances, is the ability of the recipient to control these devices. Neural interfaces are devices that aim to bridge the gap between the biological tissues and the robotic prosthetic. In most cases, the neural interface is placed on the skin, actuated by myoelectric signals highly susceptible to motion artifact and muscle signal crosstalk, ultimately preventing widespread clinical application. In 1943 Edwin Boldrey first published the transposition of nerve in bone to treat amputation neuromas. This method is still in use today, under the fundamental principal that placing the nerve in bone protects the neuroma from the mechanical and electrical stimuli that causes neuropathic pain. By re-directing transected nerves into the medullary cavity of long bones, the terminal end of the nerve is protected from external stimuli, whilst also providing direct access to the highly vascular stem cell niece. This already established surgical model presents the perfect in vivo bioreactor for the potential interfacing of transected nerves and electronic prosthetic devices. The research objectives of this pilot study were to create an animal model -termed the Osseointegrated Neural Interface (ONI), utilizing histology to demonstrate the stability and health of the nerve and surrounding tissues and electrophysiology to demonstrate nerve conductivity. METHODS: Transfemoral amputation was performed in New Zealand white rabbits. Briefly, the sciatic nerve was isolated and severed above the point of bifurcation. The femur was amputated at the midpoint and the nerve passed through a corticotomy. The terminal end of the nerve was sutured into a PDMS nerve sleeve, representing a mock electrode, which was pressed back into the opening of the medullary cavity forming a tight seal. The muscle and skin were closed over the femur. Animals were explored at 5 weeks via histology and electrophysiology. RESULTS: Gross examination of the ONI limb demonstrates that the nerve is stable at 5 weeks. Healthy nerve morphology can be identified by Schwann cells (S100+) along the length of the transected nerve. Cross sections of proximal portions of the nerve demonstrate the ONI nerve contains smaller myelinated axons when compared to the contralateral healthy sciatic nerve. Electrophysiology demonstrates that the nerve is alive within the bone, as demonstrated by compound action potentials. The transected nerve demonstrated action potentials equivalent to half that of the contralateral healthy nerve, which correlates with the smaller diameter of the myelinated axons in the ONI nerve. CONCLUSION: Terminal ends of amputated nerves are functional following being re-directed into the medullary cavity of the femur at 5 weeks. This result provides proof of principle for the ONI model and its ability to house functional prosthetic interfaces. Work is currently underway to test various electrodes in this model.
Membrane-interactive phospholipids (PLs), previously evaluated for activity against HIV-1 in vitro, are known to affect late steps in viral replication. Studies were done to determine the effects of PL analogs on posttranslational processing of HIV-1 proteins, binding of viral surface gp160/gp120 to CD4 receptor, and HIV-1-induced cell fusion. Results of this investigation indicated that PL alone (1-octadecanamido-2-ethoxypropyl-rac-3-phosphocholine, CP-51) and PL-AZT conjugate (1-octadecanamido-2-ethoxypropyl-rac-3-phospho-3′-azido-3′-deoxythymidine, CP-92) have no effect on HIV-1-induced syntheses or processing of gp160/gp120, pr51, p24, or p17 (including myristoylation) in infected cells. Progeny HIV-1 particles made in CP-92-treated H9IIIB cells contained gp120, pr51, and p24; however, these virus particles had reduced capacity to bind to CD4+ cells. Both CP-51 and CP-92 inhibited syncytium (cell fusion) formation between treated HIV-1-infected cells and uninfected CD4+ cells, and, they reduced HIV-1 gp160/gp120 binding to CD4+ cells and monoclonal antibody. These results suggest that anti-HIV-1 activity of PL compounds involves alteration of cell surface membranes and viral envelopes. Phospholipid compounds are a novel class of membrane interactive compounds with potential use in blocking the spread of HIV-1 infection and pathogenesis in AIDS.
Adequate pain control is necessary for optimal postsurgical recovery and humane treatment of laboratory and companion animals. Opioid drugs are currently the most potent analgesic agents available in human and veterinary medicine. Long-acting formulations of opioid drugs confer several important advantages over standard pharmaceutical preparations, especially for use in animals. A long-acting formulation of oxymorphone hydrochloride was produced by encapsulation into liposomes. Liposome-encapsulated (LE) oxymorphone was tested in a rat model of visceral postoperative pain. Rats were given one subcutaneous injection of LE oxymorphone (1.2 or 1.6 mg/kg of body weight) or standard oxymorphone (0.3 mg/kg) at the time of intestinal transection or resection. A single administration of LE oxymorphone hydrochloride was as effective for relief of postoperative pain in rats (P = 0.18), as were multiple (q4 h or q8 h) injections of 0.3 mg/kg of the standard pharmaceutical preparation. The rats given LE oxymorphone prior to intestinal resection also had significantly higher body weight at three and seven days after surgery than did rats that were given standard oxymorphone. In conclusion, LE oxymorphone was effective in treating visceral pain associated with intestinal surgery in rats. On the basis of body weight gain, rats treated with LE oxymorphone had improved recovery outcome, compared with rats treated with repeated injections of standard oxymorphone.
A 4-y-old female and 3-y-old male rhesus macaque ( Macaca mulatta), both housed in the same facility, died unexpectedly within 2 wk. Postmortem examination revealed severe gastric dilation in both macaques and gastric emphysema in the female macaque. Histologically, bacteria consistent with Sarcina sp. were present in both macaques within the lungs and lumen of the trachea, esophagus, and gastrointestinal (GI) tract without associated inflammation. Additionally, in the female macaque, the bacteria were found in the gastric mucosa and associated with emphysematous spaces in the gastric wall without associated inflammation. PCR and Sanger sequencing of amplicons were subsequently performed on GI contents and non-alimentary tissues from the 2 affected monkeys and on comparative samples from unaffected rhesus monkeys in the same facility and an adjacent primate facility. The cases were compared using the 2-tailed Fisher exact test ( p-value at 95% confidence). PCR identified Sarcina in GI contents of both affected and unaffected monkeys ( p = 0.6084) and in non-alimentary tissues of affected monkeys only ( p = 0.0083). These results suggest that the presence of Sarcina sp. in non-alimentary tissues is associated with gastric distension, gas accumulation, and unexpected death in nonhuman primates.
Ulcerative dermatitis (UD) is a common cause of morbidity and euthanasia in mice with a C57BL/6 (B6) background. The purposes of the current study were to determine whether UD lesions could be reliably produced in B6 mice lacking stearoyl-CoA desaturase 1 (SCD1(-/-) mice), to ascertain whether the UD lesions in SCD1(-/-) mice were similar to those found in other B6 mice, and to characterize the cell invasion phenotype of Staphlococcus xylosus cultured from the lesions. S. xylosus isolates from the environment and human skin were used as controls. SCD1(-/-) (n = 8 per group) and nontransgenic B6 control mice (n = 22 mice pooled from 3 groups that received different concentrations of conjugated linoleic acid) were fed standard rodent chow or a semipurified diet (NIH AIN76A) for 4 wk. Samples from other B6 mice with UD (field cases; n = 7) also were submitted for histology and culture. All of the SCD1(-/-) mice developed UD lesions by 4 wk on NIH AIN76A. None of SCD1(-/-) fed standard rodent chow and none of the wildtype B6 mice fed NIH AIN76A developed UD. Supplementation with conjugated linoleic acid did not affect ulcerogenesis. UD lesions in SCD1(-/-) mice and field cases were grossly and histologically similar. S. xylosus was isolated from SCD1(-/-) mice with UD (71%) and field cases of UD (43%). These isolates were the most cell-invasive, followed by the environmental isolate, and finally the human skin isolate. Our results provide a basis for further pathologic and clinical study of UD.
