Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification

Cyclin D1 proto-oncogene is a key regulator of the mammalian cell-cycle acting at the restriction point in late G1. Amplification of the cyclin D1 locus, located on chromosome 11q13, as well as cyclin D1 protein overexpression have been reported in several human malignancies. The purpose of this study was to evaluate cyclin D1 gene copy status and protein expression during the multistep process of head and neck tumorigenesis, using a combination of fluorescence in situ hybridization and immunohistochemistry techniques. From 29 selected patients presenting with head and neck squamous carcinoma and whose tumor cytospins had been previously screened for presence (16 cases) or absence (13 cases) of amplification at the 11q13 band, we analysed 46 paraffin-embedded tissue specimens that demonstrated, besides the primary tumor, the presence of contiguous adjacent normal tissue and/or premalignant lesions. Of the 16 amplified cases, nine demonstrated a continuous progression from premalignant to invasive carcinoma and seven (77.7%) of these cases showed cyclin D1 gene amplification in premalignant lesions prior to development of invasive carcinoma. Increased cyclin D1 protein expression was observed in all 16 amplified tumors and five of the 13 (38.4%) non-amplified tumors. Interestingly, dysregulated cyclin D1 expression was also found in the premalignant lesions adjacent to all 16 amplified tumors, and it appeared to precede cyclin D1 gene amplification. In contrast no dysregulated expression was detected in the premalignant lesions of the non-amplified tumors. In conclusion, these findings provide strong evidence for early dysregulation of cyclin D1 expression during the tumorigenesis process and suggest that dysregulated increased expression precedes and possibly enables gene amplification.     

Gallstones and isoflurane hepatitis

OBJECTIVES: To assess the level of satisfaction of physicians in provincial psychiatric hospitals with Review Boards (RBs) regarding Civil Commitment Certificates (CCCs), Certificates of Incompetence (COIs), and Treatment Orders (TOs). METHOD: A total of 200 survey questionnaires were distributed to physicians in provincial psychiatric hospitals. Ninety surveys (completed by 25 females, 45 males, and 20 unknown gender) were returned, representing a 45% return rate. Because of their assignments (for example, outpatient department), not all physicians were involved with RBs, and the return rate is likely to have been influenced by this factor. RESULTS: Physician satisfaction rates of 58.2% for CCCs, 66.7% for COIs, and 70.0% for TOs were obtained. Stepwise multiple regression analysis showed that the level of physician satisfaction with RBs for CCCs was predicted best (44.7% of variance) by physician level of comfort with certification and years of institutional affiliation. Qualitative physician responses revealed 3 major themes: patient-related issues, physician-related issues, and RB structure- and process-related issues. CONCLUSIONS: Strategies that increase physician comfort level with RBs and changes in the medicolegal structure and process are discussed. A similar survey of patients and RB members is recommended.     

Influence of short-term dietary measures on dioxin concentrations in human milk

Breast-feeding may expose infants to high levels of toxic chlorinated dioxins. To diminish intake of these lipophilic compounds by the baby, two diets were tested for their ability to reduce concentrations of dioxins in human milk. The diets were a low-fat/high- carbohydrate/low-dioxin diet. (about 20% of energy intake derived from fat) and a high fat /low-carbohydrate/low-dioxin diet. These diets were tested in 16 and 18 breast-feeding women, respectively. The test diets were followed for 5 consecutive days in the fourth week after delivery. Milk was sampled before and at the end of the dietary regimen, and dioxin concentrations and fatty acid concentrations were determined. Despite significant influences of these diets on the fatty acid profiles, no significant influence on the dioxin concentrations in breast milk could be found. We conclude that short-term dietary measures will not reduce dioxin concentration in human milk.     

CHILD syndrome with linear eruptions, hypopigmented bands, and verruciform xanthoma

The traditional rhomboid transposition flap has been widely used in reconstructive surgery. The authors have modified the original technique by eliminating the creation of the rhomboid defect and by directly transposing the flap into the original postexcisional defect. These changes allow maximum flexibility in flap design and minimize normal tissue loss. The authors retrospectively reviewed the charts of patients who underwent periocular reconstruction with flaps from 1990 through 1995. The authors selected those patients in whom the modified rhomboid flap was used. Functional and cosmetic results and complications were reviewed. Two hundred thirty-two patients were identified in whom 242 flaps were performed. The modified rhomboid flap was used in 101 patients (41.7%). Complications occurred in 23 patients (23%), 19 of whom (19%) were treated medically and four of whom (4%) required an additional surgical procedure. Cosmetic and functional results were classified as very good or excellent in 96 patients (96%). The use of a modified rhomboid flap in the reconstruction of the periocular area offers ample versatility in flap design and minimal normal tissue loss. Functional and cosmetic results are satisfactory in the vast majority of cases.     

Ventilatory management in the postanesthesia care unit

Postoperative ventilatory depression is common in patients who have received intravenous and inhalational anesthetic agents. Prompt assessment and treatment of ventilatory depression are essential to minimize morbidity and mortality.     

Predicting length of stay in an acute psychiatric hospital

OBJECTIVE: Multivariate statistical methods were used to identify patient-related variables that predicted length of stay in a single psychiatric facility. The study investigated whether these variables remained stable over time and could be used to provide individual physicians with data on length of stay adjusted for differences in clinical caseloads and to detect trends in the physicians' practice patterns. METHODS: Data on all patients discharged over two six-month periods were collected at an acute psychiatric inpatient facility. Stepwise multiple regression analyses were conducted on the two datasets. RESULTS: The results from both analyses revealed that five variables significantly predicted length of stay and were stable over time. They were a primary diagnosis of schizophrenia, the number of previous admissions, a primary diagnosis of a mood disorder, age, and a secondary diagnosis of an alcohol- or other drug-related disorder. For some physicians, the mean length of stay of their patients differed significantly from the length predicted by the regression model--generally, it was shorter. CONCLUSIONS: The results demonstrate that patient-related predictors of length of stay in a single psychiatric hospital can be identified using relatively simple statistical procedures and can be consistent across a large dataset and over time.     

Mechanism of irreversible inactivation of phosphomannose isomerases by silver ions and flamazine

Silver ions and silver-containing compounds have been used as topical antimicrobial agents in a variety of clinical situations. We have previously shown that the enzyme phosphomannose isomerase (PMI) is essential for the biosynthesis of Candida albicans cell walls. In this study, we find that PMI can be inhibited by silver ions. This process is shown to be irreversible, and is a two-step process, involving an intermediate complex with a dissociation constant, Ki, of 59 +/- 8 microM, and a maximum rate of inactivation of 0.25 +/- 0.04 min-1 in 50 mM Hepes buffer, pH 8.0 at 37 degrees C. The enzyme can be protected against this inactivation by the substrate mannose 6-phosphate, with a dissociation constant of 0.31 +/- 0.04 mM, close to its Km value. Flamazine (silver sulfadiazine) is a silver-containing antibiotic which is used clinically as a topical antimicrobial and antifungal agent. We compared the ability of silver sulfadiazine and two other silver-containing compounds to irreversibly inactivate C. albicans PMI. The addition of the organic moiety increased the affinity of the compounds, with silver sulfadiazine showing a Ki of 190 +/- 30 nM. In all cases, the maximum inhibition rate was similar, implying a similar rate-determining step. Silver sulfadiazine does not inhibit Escherichia coli PMI, and this suggests a role of the only free cysteine, Cys-150, in the inactivation process. To confirm this, we mutated this residue to alanine in C. albicans PMI. The resultant Cys150 --> Ala mutant protein showed similar Vm and Km values to the wild-type enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons

Recent studies show that the cytokine interleukin-6 (IL-6) is expressed at elevated levels in the CNS in several disease states and contributes to the neuropathological process. The mechanisms through which IL-6 exerts its CNS effects are primarily unknown. We have investigated the pathophysiological effects of IL-6 on developing CNS neurons using a culture model system and a chronic treatment paradigm. Here, we show, using current- and voltage-clamp recordings, that chronic IL-6 treatment of developing cerebellar granule neurons increases the membrane and current response to NMDA and that these effects are the primary mechanism through which IL-6 produces an enhanced calcium signal to NMDA. We also show that calcium influx through voltage-sensitive calcium channels contributes to the enhanced calcium signal to NMDA in the IL-6-treated neurons in a developmentally regulated manner and that the membrane depolarization to NMDA is more sensitive to the NMDA receptor antagonist ifenprodil in the IL-6-treated neurons compared with control neurons at a late developmental stage, consistent with a larger proportion of NMDA receptors containing the NMDAR2B subunit in the IL-6-treated neurons. Additional studies show that IL-6 treatment reduces the number of granule neurons in culture and enhances neurotoxicity involving NMDA receptors. These results support a pathological role for IL-6 in the CNS and indicate that NMDA receptor-mediated functions are likely to play a critical role in neuropathological changes observed in CNS diseases associated with elevated CNS levels of IL-6.