New advances in treating osteoporotic compression fractures.

Osteoporosis is a chronic and potentially debilitating disease. A painful consequence of osteoporosis is a compression fracture of a vertebral body of the spine. These fractures can lead to physical deformities and emotional trauma. Treatment options for these fractures are limited and occasionally ineffective. New surgical advances in treating vertebro-compression fractures are evolving. Kyphoplasty is a new surgical procedure now being used to treat the painful compression fracture.     

Inhibition of cytochrome P-450c-mediated benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase by dihydrosafrole

1. Inhibitory activity of dihydrosafrole towards benzo[a]pyrene (BP) hydroxylase activity in hepatic microsomes from beta-naphthoflavone (BNF)-induced rats, and in reconstituted systems containing cytochrome P-450c, increased dramatically on preincubation of the inhibitor with NADPH; no inhibition occurred without preincubation. The level of BP hydroxylase inhibition was associated with the progressive formation of the 456 nm dihydrosafrole metabolite-cytochrome P-450c spectral complex during preincubation. 2. Inhibition of BP hydroxylase by dihydrosafrole in control microsomes, and inhibition of ethoxyresorufin O-deethylase (EROD) in microsomes (control or BNF-induced) and in reconstituted systems with cytochrome P-450c, did not require preincubation and apparently was not dependent on prior formation of the dihydrosafrole metabolite-cytochrome P-450 complex. 3. Kinetic studies established that, following preincubation with NADPH, dihydrosafrole was a noncompetitive inhibitor of both BP hydroxylase and EROD activities. In the absence of preincubation, dihydrosafrole was an effective competitive inhibitor of EROD in BNF-induced microsomes and in reconstituted systems with cytochrome P-450c. 4. Both ethoxyresorufin and benzo[a]pyrene inhibited the development of the type I optical difference spectrum of dihydrosafrole in reconstituted systems containing cytochrome P-450c. Inhibition by ethoxyresorufin was competitive while that caused by benzo[a]pyrene was noncompetitive in nature. 5. The type II ligand phenylimidazole was an effective noncompetitive inhibitor of EROD activity but failed to exert any inhibitory effect on cytochrome P-450c-mediated BP hydroxylase activity. Phenylimidazole inhibited formation of the dihydrosafrole type I optical difference spectrum non-competitively. 6. The results indicate that ethoxyresorufin and benzo[a]pyrene may occupy different binding sites on cytochrome P-450c and that dihydrosafrole binds primarily to the site utilized by ethoxyresorufin.     

TGF-beta promotes the establishment of renal cell carcinoma bone metastasis.

Bone metastases develop in approximately 30% of patients with RCC, and the mechanisms responsible for this phenomenon are unknown. We found that TGF-beta1 stimulation of RCC bone metastasis cells promotes tumor growth and bone destruction possibly by stimulating paracrine interactions between tumor cells and the bone. INTRODUCTION: Bone metastasis is a frequent complication and causes marked morbidity in patients with renal cell carcinoma (RCC). Surprisingly, the specific mechanisms of RCC interaction with bone have been scarcely studied despite the inability to prevent or effectively treat bone metastasis. Bone is a reservoir for various growth factors including the pleiotropic cytokine TGF-beta1. TGF-beta1 has been shown to have tumor-supportive effects on advanced cancers and evidence suggests its involvement in promoting the development of breast cancer bone metastasis. Here, we studied the potential role of TGF-beta1 in the growth of RCC bone metastasis (RBM). MATERIALS AND METHODS: To inhibit TGF-beta1 signaling, RBM cells stably expressing a dominant-negative (DN) TGF-betaRII cDNA were generated. The in vivo effect of TGF-beta1 on RBM tumor growth and osteolysis was determined by histological and radiographic analysis, respectively, of athymic nude mice after intratibial injection of parental, empty vector, or DN RBM cells. The in vitro effect of TGF-beta1 on RBM cell growth was determined after TGF-beta1 treatment by MTT assay. RESULTS: TGF-beta1 and the TGF-beta receptors I and II (TGF-betaRI/II) were consistently expressed in both RBM tissues and cell lines. Inhibition of TGF-beta1 signaling in RBM cells significantly reduced tumor establishment and osteolysis observed in vivo after injection into the murine tibia, although no effect on tumor establishment was observed after injection of RBM cells subcutaneously or into the renal subcapsule. Treatment of five RBM cell lines with TGF-beta1 in vitro either had no effect (2/5) or resulted in a significant inhibition (3/5) of cell growth, suggesting that TGF-beta1 may promote RBM tumor growth indirectly in vivo. CONCLUSIONS: TGF-beta1 stimulation of RBM cells plays a role in promoting tumor growth and subsequent osteolysis in vivo, likely through the initiation of tumor-promoting paracrine interactions between tumor cells and the bone microenvironment. These data suggest that inhibition of TGF-beta1 signaling may be useful in the treatment of RBM.     

The outcome of ganglion clipping in hyperhidrosis and blushing

A total of 114 patients with various sympathetic disorders underwent endoscopic sympathetic block over different thoracic ganglions by the clipping method. The advantages of this method include the recognition of the clipped level, changeability, and reversibility. However, 4.4% of patients were unilaterally clipped at the wrong level.     

Particle size and morphology of UHMWPE wear debris in failed total knee arthroplasties--a comparison between mobile bearing and fixed bearing knees.

Osteolysis induced by ultrahigh molecular weight polyethylene wear debris has been recognized as the major cause of long-term failure in total joint arthroplasties. In a previous study, the prevalence of intraoperatively identified osteolysis during primary revision surgery was much higher in mobile bearing knee replacements (47%) than in fixed bearing knee replacements (13%). We postulated that mobile bearing knee implants tend to produce smaller sized particles. In our current study, we compared the particle size and morphology of polyethylene wear debris between failed mobile bearing and fixed bearing knees. Tissue specimens from interfacial and lytic regions were extracted during revision surgery of 10 mobile bearing knees (all of the low contact stress (LCS) design) and 17 fixed bearing knees (10 of the porous-coated anatomic (PCA) and 7 of the Miller/Galante design). Polyethylene particles were isolated from the tissue specimens and examined using both scanning electron microscopy and light-scattering analyses. The LCS mobile bearing knees produced smaller particulate debris (mean equivalent spherical diameter: 0.58 microm in LCS, 1.17 microm in PCA and 5.23 microm in M/G) and more granular debris (mean value: 93% in LCS, 77% in PCA and 15% in M/G).     

Evolution of Learning in Three Aplysiid Species: Differences in Heterosynaptic Plasticity Contrast with Conservation in Serotonergic Pathways

We investigated the neurobiological basis of variation in sensitization between three aplysiid species: Aplysia californica , Phyllaplysia taylori and Dolabrifera dolabrifera . We tested two different forms of sensitization induced by a noxious tail shock: local sensitization, expressed near the site of shock, and general sensitization, tested at remote sites. Aplysia showed both local and general sensitization, whereas Phyllaplysia demonstrated only local sensitization, and Dolabrifera lacked both forms of learning. We then investigated a neurobiological correlate of sensitization, heterosynaptic modulation of sensory neuron excitability by tail-nerve stimulation. We found (1) an increase in sensory neuron (SN) excitability after both ipsilateral and contralateral nerve stimulation in Aplysia , (2) a smaller and shorter-lasting increase in Phyllaplysia , and (3) no effect in Dolabrifera . Because sensitization in Aplysia is strongly correlated with serotonergic (5-HT) neuromodulation, we hypothesized that the observed interspecific variation in sensitization and SN neuromodulation might be correlated with variation in the anatomy and/or functional response of the serotonergic system. However, using immunohistochemistry, we found that all three species showed a similar pattern of 5-HT innervation. Furthermore, they also showed comparable 5-HT release evoked by tail-nerve shock, as measured with chronoamperometry. These observations indicate that interspecific variation in learning is correlated with differences in SN heterosynaptic plasticity within a backgound of evolutionary conservation in the 5-HT neuromodulatory pathway. We thus hypothesize that evolutionary changes in learning phenotype do not involve modifications of the 5-HT pathway per se , but rather, changes in the response of SNs to the activation of this or other neuromodulatory pathways upon noxious stimulation.     

MR image segmentation using vector decomposition and probability techniques: A general model and its application to dual-echo images

A general model is developed for segmenting magnetic resonance images using vector decomposition and probabilfty techniques. Each voxel is assigned fractional volumes of q tissues from p differently weighted images (q ≤ p + 1) in the presence of partial-volume mixing, random noise, and other tissues. Compared wtth the eigenimage method, fewer differently weighted images are needed for segmenting the q tissues, and the contrast-to-noise ratio in the calculated fractional volumes is improved. The model can produce com-posrte tissue-type images similar to that of the probability methods, by comparing the fractional volumes assigned to different tissues on each voxel. A three-tissue (p = 2, q = 3) model is illustrated for segmenting three tissues from dual-echo images. M provides statistical analysis to the algebraic method. A three-compartment phantom is segmented for validation. Two clinical examples are presented.     

A rare polymorphism affects a mitogen-activated protein kinase site in synapsin III: possible relationship to schizophrenia.

BACKGROUND: Synapsin III plays a role in neuronal plasticity and maps to chromosome 22q12-13, a region suggested to be linked to schizophrenia. To determine if synapsin III plays a role in this disease, we searched for polymorphisms in this gene in patients with schizophrenia and controls. METHODS: The synapsin III gene was initially sequenced from 10 individuals with schizophrenia to identify polymorphisms. Association analysis was then performed using 118 individuals with schizophrenia and 330 population controls. Synapsin III expression was studied by immunoblot analyses, and phosphorylation sites were mapped by sequencing trypsin-digested synapsin III fragments phosphorylated with phosphorus-32. RESULTS: A rare, missense polymorphism, S470N, was identified in the synapsin III gene and appeared more frequently in individuals with schizophrenia than in controls (p =.0048). The site affected by the polymorphism, Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. Phosphorylation at Ser470 was increased during neonatal development and in response to neurotrophin-3 in cultured hippocampal neurons. CONCLUSIONS: Our observations suggest an association of a rare polymorphism in synapsin III with schizophrenia, but further studies will be required to clarify its role in this disease.     

Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone.

The authors conducted a retrospective analysis of 1178 patients with histologically proven invasive carcinoma of the uterine cervix treated with irradiation alone. The minimum follow-up time was 3 years. The 10-year actuarial pelvic failure rate in Stage IB was 6% for tumors less than 3 cm, 15% for tumors 3 to 5 cm, and 30% for tumors more than 5 cm (P = 0.0018). The 10-year actuarial pelvic failure rate in Stage IIA was 10% for tumors less than 3 cm, 28% for tumors 3 to 5 cm, and 20% for tumors more than 5 cm (P = 0.09). Stage IIB unilateral nonbulky tumors (less than 5 cm) had a 20% pelvic failure rate compared with 28% for bilateral lesions and 35% for unilateral bulky tumors (more than 5 cm) (P = 0.35). In Stage IIB, pelvic failures were greater when disease extended into the lateral parametrium (30%) compared with medial parametrial involvement only (17%) (P = 0.01). In Stage III unilateral nonbulky tumors, the pelvic failure rate was 28% compared with 45% to 50% for unilateral bulky lesions (P = 0.002). Bilateral parametrial disease in Stage IIB did not increase the pelvic failure rate (21% in both subgroups) (P = 0.83), whereas in Stage III, bilateral parametrial involvement was associated with a 48% pelvic failure rate versus 28% for unilateral extension (P less than or equal to 0.01). Five-year disease-free survival (DFS) rates for IB tumors less than or equal to 3 cm was 90% versus 67% for tumors more than 3 cm (P = 0.01). In Stage IIA tumors less than or equal to 3 cm, 5-year DFS was 70% versus 45% for tumors more than 3 cm. Patients with Stage IIB nonbulky tumors (less than or equal to 5 cm in diameter) had better 10-year DFS (65% to 70%) compared with those with bilateral bulky tumors (45% to 55%) (P = 0.10). Stage III patients with unilateral nonbulky tumors had a 55% 10-year DFS compared with 35% to 40% for bulky tumors or bilateral parametrial involvement (P = 0.002). The authors concluded that clinical stage and size of tumor are critical factors in the prognosis, therapy selection, and evaluation of results in carcinoma of the uterine cervix.