Experimental model of pudendal nerve innervation of a skeletal muscle neosphincter for faecal incontinence

BACKGROUND: Faecal incontinence is difficult to treat. A variety of reconstructive procedures has been described, but none is entirely satisfactory. This study evaluated the feasibility of cross-innervating a skeletal muscle neosphincter with the pudendal nerve in a canine model. METHODS: Thirty dogs were rendered surgically incontinent (the pudendal nerve was cut and the external sphincter was partially excised). A neosphincter was then created using the semitendinosus muscle. In ten dogs pudendal nerve transposition (PNT) to the nerve to the semitendinosus muscle was performed. Ten dogs were given a dynamic neosphincter by inserting a pulse generator at 6 weeks. The remaining ten dogs served as controls with passive semitendinosus wraps. Anal manometry was performed before operation and monthly for 5 months. Muscle biopsies, performed at the initial operation and at 5 months, were stained for slow- and fast-twitch fibres, and were examined histologically. RESULTS: At 1 month, mean sphincter function was 32 per cent of the preoperative value in the control animals, 34 per cent in the PNT group and 27 per cent in the electrostimulation group; all dogs were incontinent. At 5 months the mean recovery of sphincter function was 42 per cent of the preoperative value in controls, 100 per cent in dogs with PNT (P < 0.001) and 63 per cent in dogs having electrostimulation (stimulator on) (P = 0.02). Six dogs with PNT had squeeze pressures equal to or greater than preoperative levels. At 5 months the ratio of slow to fast fibres was significantly greater in all dogs (control P = 0.01, PNT P < 0.005, electrostimulation P < 0.001). CONCLUSION: Use of the pudendal nerve to innervate a canine skeletal muscle anal wrap produced a functional anal sphincter that was superior to electrically stimulated and passive wraps.     

Neuroanatomy of the pain system and of the pathways that modulate pain

We review many of the recent findings concerning mechanisms and pathways for pain and its modulation, emphasizing sensitization and the modulation of nociceptors and of dorsal horn nociceptive neurons. We describe the organization of several ascending nociceptive pathways, including the spinothalamic, spinomesencephalic, spinoreticular, spinolimbic, spinocervical, and postsynaptic dorsal column pathways in some detail and discuss nociceptive processing in the thalamus and cerebral cortex. Structures involved in the descending analgesia systems, including the periaqueductal gray, locus ceruleus, and parabrachial area, nucleus raphe magnus, reticular formation, anterior pretectal nucleus, thalamus and cerebral cortex, and several components of the limbic system are described and the pathways and neurotransmitters utilized are mentioned. Finally, we speculate on possible fruitful lines of research that might lead to improvements in therapy for pain.     

P-glycoprotein function involves conformational transitions detectable by differential immunoreactivity

The MDR1 P-glycoprotein (Pgp), a member of the ATP-binding cassette family of transporters, is a transmembrane ATPase efflux pump for various lipophilic compounds, including many anti-cancer drugs. mAb UIC2, reactive with the extracellular moiety of Pgp, inhibits Pgp-mediated efflux. UIC2 reactivity with Pgp was increased by the addition of several Pgp-transported compounds or ATP-depleting agents, and by mutational inactivation of both nucleotide-binding domains (NBDs) of Pgp. UIC2 binding to Pgp mutated in both NBDs was unaffected in the presence of Pgp transport substrates or in ATP-depleted cells, whereas the reactivities of the wild-type Pgp and Pgps mutated in a single NBD were increased by these treatments to the level of the double mutant. These results indicate the existence of different Pgp conformations associated with different stages of transport-associated ATP hydrolysis and suggest trapping in a transient conformation as a mechanism for antibody-mediated inhibition of Pgp.     

Acute hemorrhagic pulmonary infarction and necrotizing pneumonia in horses: 21 cases (1967-1993)

Specimens of formalin-fixed, paraffin-embedded non-small-cell lung carcinomas (NSCLCs; n = 187) were analysed immunohistochemically for expression of cyclin A. The analysis was intended to determine whether cyclin A has additional prognostic value for predicting patients' survival and drug response. Of the 187 NSCLCs, 141 cases (75%) showed expression of cyclin A. Patients with cyclin A-positive carcinomas had significantly shorter median survival times than patients with cyclin A-negative carcinomas (79 vs 129 weeks, P = 0.045). Similar results were obtained with more homogeneous groups of patients: patients with only T3 tumours, patients with epidermoid carcinomas and patients with lymph node involvement. The clinical parameters (age, stage, histology, extent of tumour size, lymph node involvement) had no influence on expression of cyclin A. A direct correlation between cyclin A and the proportion of S-phase cells (P = 0.08) and an inverse relationship between cyclin A and the proportion of G0/G1-phase cells (P = 0.04) were found. Furthermore, a significant correlation between the expression of cyclin A and the response of NSCLC to doxorubicin in vitro was detected (P = 0.026).     

The effects of D-23129, a new experimental anticonvulsant drug, on neurotransmitter amino acids in the rat hippocampus in vitro

Recent literature continues to promote the early use of disease-modifying antirheumatic drugs (DMARDs), especially the less toxic agents such as hydroxychloroquine. Reports of combination DMARD treatments have been disappointing, and careful attention must be paid to clinical trial design if the efficacy of combination therapies is to be established. Methotrexate retains its prominent role, and its mechanism of action has been the subject of many reports; its toxicity remains the most common reason for treatment termination. Guidelines for monitoring hepatic toxicity of methotrexate have been published and may help reduce the need for invasive biopsy procedures. Significant risk factors for methotrexate pulmonary toxicity remain difficult to identify. Large placebo-controlled studies of both sulfasalazine and hydroxychloroquine have been reported and have demonstrated the efficacy of these agents in the treatment of early rheumatoid arthritis. Awareness of drug-toxicity profiles is important for physicians who prescribe these agents.     

Evidence for heme-mediated redox regulation of human cystathionine beta-synthase activity

Human cystathionine beta-synthase catalyzes the first step in the catabolic removal of the toxic metabolite, homocysteine. It is unique in being dependent on both pyridoxal phosphate (PLP) and heme for activity. The reaction involves condensation of serine and homocysteine to give cystathionine. Although the role of PLP can be rationalized in analogy with other PLP-dependent enzymes that catalyze beta-replacement reactions, the role of the heme is unknown. In this study, we have purified and characterized the recombinant human enzyme and have examined the effect of heme oxidation state on enzyme activity. We find that under reducing conditions, generated by addition of titanium citrate, the enzyme exhibits a 1.7-fold lower activity than under oxidizing conditions. Reoxidation of the ferrous enzyme with ferricyanide results in alleviation of inhibition. This redox-linked change in enzyme activity correlates with changes in heme oxidation state monitored by UV-visible spectroscopy. Dithiothreitol, which does not reduce the enzyme-bound heme, does not perturb enzyme activity. These studies provide the first evidence for redox-linked regulation of cystathionine beta-synthase which is heme-dependent.