High affinity of sigma1-binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C8–C7 isomerase

1. The sigma-drug binding site of guinea-pig liver is carried by a protein which shares significant amino acid sequence similarities with the yeast sterol C₈–C₇ isomerase (ERG2 protein). Pharmacologically - but not structurally - the sigma₁-site is also related to the emopamil binding protein, the mammalian sterol C₈–C₇ isomerase. We therefore investigated if sterol C₈–C₇ isomerase inhibitors are high affinity ligands for the (+)-[³H]-pentazocine labelled sigma₁-binding site.
2. Among the compounds which bound with high affinity to native hepatic and cerebral as well as to yeast expressed sigma₁-binding sites were the agricultural fungicide fenpropimorph (K_i 0.005 nM), the antihypocholesterinaemic drugs triparanol (K_i 7.0 nM), AY-9944 (K_i 0.46 nM) and MDL28,815 (K_i 0.16 nM), the enantiomers of the ovulation inducer clomiphene (K_i 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (K_i 26 nM).
3. Except for tamoxifen these affinities are essentially identical with those for the [³H]-ifenprodil labelled sterol C₈–C₇ isomerase of S. cerevisiae. This demonstrates that sigma₁-binding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its affiliations with yeast and mammalian sterol isomerases we propose that the sigma₁-binding site is localized on a sterol isomerase related protein, involved in postsqualene sterol biosynthesis.

     

HLA-D Antigen Expression and Langerhans' Cell Infiltrates in Thyroid Tumors

Papillary carcinomas (PCs) of thyroid are among the most common but least aggressive human malignancies. The factors explaining the indolence of these tumors are unknown but host-tumor immune interactions may play a role. This study was designed to determine if there is morphologic evidence of these. Frozen tissues collected from 21 PCs, 4 follicular adenomas (FAs), 4 follicular carcinomas (FCs), and 11 nodular hyperplasias (NHs) were stained immunohistochemically for HLA-D antigens, lymphocyte and macrophage markers; results were graded numerically. Paraffin-embedded tumors (35 PCs, 10 FAs, and 10 FCs) were stained for S-100 protein to detect Langerhans' cells (LCs). Diffuse staining for HLA-D antigens and heavy mononuclear infiltrates were found more commonly in PCs compared to follicular neoplasms (FNs) or NHs. No consistent relationship was found between lymphocyte/macrophage infiltrates and expression of HLA-D antigens. The largest number of LCs was in PCs (median 11.8 cells/standard microscopic field [c/smf]), fewer cells were found in FA (3.7 c/smf), and the least in FC (0.05 c/smf). Features of host-tumor interaction including HLA-D expression and infiltrates with lymphocyte macrophages and LC are more strongly expressed in PC than other tumors. This may play a role in explaining their biological behavior.     

Surgical anaesthesia for Caesarean section with a subdural catheter

Purpose

This case report describes a radiologically proven subdural catheter placed in a term parturient, which consistently performed as an epidural catheter for both labour analgesia as well as surgical anaesthesia.

Clinical features

The patient was a 26-yr-old, 52.7 kg, 140 cm healthy woman with a 39 wk intrauterine pregnancy. At initiation of epidural blockade, and for many hours throughout labour, an appropriate volume and concentration of local anaesthetic achieved an appropriate analgesic sensory level (10 ml bupivacaine 0.25%, bilateral T₁₀ sensory level). However, for Caesarean section, while an appropriate volume and concentration of local anaesthetic achieved an appropriate surgical anaesthetic sensory level (15 ml bupivacaine 0.5%, bilateral T₄ sensory level), there was no demonstrable motor blockade (0 on the Bromage scale). The Caesarean section was performed without incident, and without the need for supplemental intravenous opioids or anxiolytics.

Conclusion

We report the case to question the commonly held beliefs of subdural catheter presentation. We questioned the catheter position, and proved its subdural placement, only after larger volumes of higher concentration local anaesthetic did not achieve expected goals. It is possible that a high percentage of epidural catheters may be subdural, unbeknownst to the practitioner.     

Decision-making process in abdominal surgery in the geriatric patient

The high rates of abdominal disorders in a growing population of geriatric patients and the greater willingness of the surgeon to cope with major problems in the elderly are factors contributing to a steady increase in abdominal procedures in this group. Four hundred consecutive major abdominal surgical procedures in patients over 70 years of age were submitted for computer analysis, the purpose of which was to determine the principal factors affecting mortality and morbidity. The etiological profile of abdominal surgery in the elderly was characterized by a high percentage of procedures related to the biliary tract, with the second largest group being those for intestinal obstruction due to benign and malignant conditions. The decision-making process in geriatric surgery is of great importance, requiring consideration of ethical, medico-legal and economic factors in addition to the purely medical ones. Analysis of data presented in this series leads to the following conclusions:

1. There is a declining mortality rate in all elective operations in the elderly, in the absence of widespread malignancy.
2. Timing is all important in abdominal emergencies in the elderly, and early operations are usually more successful than either immediate or delayed operations.
3. Definitive procedures are sometimes both safer and more cost effective than minimal procedures performed under such circumstances.
4. The principal factors leading to high mortality rates are the presence of malignancy, generalized peritonitis, and moderate-to-severe involvement of life-support systems.

     

Species differences in activating and inactivating enzymes related to the control of mutagenic metabolites

Microsomal monooxygenases catalyze the biosynthesis of epoxides from olefinic and aromatic compounds whilst microsomal epoxide hydratase and cytoplasmic glutathione S-transferases are responsible for their further biotransformation. Although catalytically very efficient the cytoplasmic glutathione S-transferases play, due to their subcellular localization, a minor role in the inactivation of epoxides derived from large lipophilic compounds and were, therefore, not included in this study. It was shown with such a lipophilic compound, benzo(a)pyrene, as a model substance and with liver enzyme mediated bacterial mutagenesis as biological endpoint that species and strain differences in epoxide hydratase and monooxygenases are reflected in very dramatic differences in mutagenicity of benzo(a)pyrene which varied from extremely potent to a degree which could easily be overlooked. In order to investigate whether the differences in enzyme activities were causally linked to the observed differences in mutagenicity, the enzyme activities were modulated by inhibition and induction. These manipulations were always accompanied by the corresponding changes in mutagenicity.It is concluded that species such as mice which possess high monooxygenase activity but very low epoxide hydratase activity are much more susceptible than man to those toxic effects which are mediated by metabolically formed epoxides which are substrates of epoxide hydratase. In this regard, it is especially noteworthy that mice possess a much lower hepatic epoxide hydratase activity than man.Presented at the Symposium Influence of Metabolic Activations and Inactivations on Toxic Effects held at the 18th Spring Meeting of the Deutsche Pharmakologische Gesellschaft, Section Toxicology, D-6500 Mainz, March 15, 1977     

Phantom tooth pain: a new look at an old dilemma

The aim of this paper is to review the current knowledge of phantom tooth pain, a neuropathic facial pain disorder, thought to result from peripheral nerve injury. Phantom tooth pain is a deafferentation pain disorder of persistent toothache in teeth that have been denervated (usually by root canal treatment) or pain in the area formerly occupied by teeth prior to their extraction. The pain usually extends to the facial structures adjacent to tissues that have undergone deafferentation. The clinical characteristics, differential diagnosis, epidemiology, and treatment of phantom tooth pain are reviewed. Suggestions for further research include the need for controlled treatment trials and modification of current criteria. CONCLUSIONS: Phantom tooth pain has much in common with other phantom pain disorders. In the absence of controlled clinical trials specifically directed to phantom tooth pain, treatment should be guided by standards used for other neuropathic pain disorders. Revised diagnostic criteria for phantom tooth pain are proposed.     

Seroreactivity to human papillomavirus (HPV) types 16, 18, or 31 and risk of subsequent HPV infection: results from a population-based study in Costa Rica.

Whether antibodies to human papillomavirus (HPV) capsids, elicited by natural infection, are protective is unknown. This question was addressed in a population-based cohort of 7046 women in Costa Rica by examining the association between baseline seroreactivity to HPV-16, HPV-18, or HPV-31 virus-like particles and the risk of subsequent HPV infection at a follow-up visit 5-7 years after enrollment. Seropositivity to HPV-16, HPV-18, or HPV-31 was not associated with a statistically significant decreased risk of infection with the homologous HPV type [relative risk (RR) and [95% confidence interval (CI)], 0.74 (0.45-1.2), 1.5 (0.83-2.7), and 0.94 (0.48-1.8), respectively]. Seropositivity to HPV-16 or HPV-31 was not associated with a decreased risk of infection with HPV-16 or its genetically related types [RR (95% CI), 0.82 (0.61-1.1) and 0.93 (0.68-1.2), respectively]. Seropositivity to HPV-18 was not associated with a decreased risk of infection with HPV-18 or its genetically related types (RR 1.3; 95% CI 1.0-1.8). Thus, we did not observe immunity, although a protective effect from natural infection cannot be excluded because of the limits of available assays and study designs.     

Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis.

PURPOSE: Radiation-induced fibrosis (RIF) is a rare morbid complication of radiotherapy, without an established method of management. RIF treatment with a combination of pentoxifylline (PTX) and alpha-tocopherol (vitamin E; Vit E) was recently prompted by the good results of a clinical trial and an animal study. The present double-blind, placebo-controlled, monocentric study was designed to assess the efficacy of this combination in treating RIF sequelae. PATIENTS AND METHODS: Twenty-four eligible women with 29 RIF areas involving the skin and underlying tissues were enrolled from December 1998 to April 2000. These patients, previously irradiated for breast cancer, were randomly assigned to four balanced treatment groups: (A) 800 mg/d of PTX and 1,000 U/d of Vit E; (B) PTX plus placebo; (C) placebo plus Vit E; and (D) placebo-placebo. The main end point measure was the relative regression of measurable RIF surface after 6 months of treatment. Assessment was completed by depth (with ultrasonography) and associated symptom measures. RESULTS: Twenty-two patients with 27 RIF areas were analyzed at 6 months. Mean RIF surface regression was significant with combined PTX/Vit E versus double placebo (60% +/- 10% v 43% +/- 17%; P =.038). The median slope for the speed of RIF surface area and volume regression was significantly higher for group A than groups B, C, and D. All treatments were well tolerated. CONCLUSION: Six months' treatment of combined PTX/Vit E can significantly reduce superficial RIF. Synergism between PTX and Vit E is likely, as treatment with each drug alone is ineffective, but these results require confirmation in larger series.     

Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma.

PURPOSE: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.