Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).

BACKGROUND: We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a major issue surrounding PCI, we report here midterm and long-term repeated evaluation of neurocognitive functions and quality of life (QoL). PATIENTS AND METHODS: At predetermined intervals, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and brain module were used for self-reported patient data, whereas the EORTC-Radiation Therapy Oncology Group Late Effects Normal Tissue-Subjective, Objective, Management, Analytic scale was used for clinicians' assessment. For each scale, the unfavourable status was analysed with a logistic model including age, grade at baseline, time and PCI dose. RESULTS: Over the 3 years studied, there was no significant difference between the two groups in any of the 17 selected items assessing QoL and neurological and cognitive functions. We observed in both groups a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory (all P < 0.005). CONCLUSION: Patients should be informed of these potential adverse effects, as well as the benefit of PCI on survival and BM. PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC.

Nuclear Thimet oligopeptidase is coexpressed with oestrogen receptor alpha in hypothalamic cells and regulated by oestradiol in female mice.

Thimet oligopeptidase (EC 3.4.24.15; also called EP24.15 and TOP; referred to here as TOP) is a neuropeptidase involved in the regulation of several physiological functions including reproduction. Among its substrates is gonadotrophin-releasing hormone (GnRH), an important hypothalamic hormone that regulates the synthesis and release of oestradiol and facilitates female sexual behaviour. Using immunohistochemistry, we found that TOP is expressed in the nucleus of cells throughout the female mouse brain, and in high levels in steroid-sensitive regions of the hypothalamus, which is consistent with previous findings in male rats. Furthermore, dual-label immunofluorescence revealed that TOP and oestrogen receptor alpha (ERalpha) coexpress in several reproductively-relevant brain regions, including the medial preoptic area (mPOA), arcuate nucleus (ARC), ventrolateral portion of the ventromedial hypothalamic nucleus (VMNvl) and the midbrain central grey (MCG). Previous studies in rats have shown that oestradiol decreases hypothalamic TOP levels or activity, possibly potentiating the effects of GnRH. In the present study, analysis by immunohistochemistry revealed that oestradiol decreased TOP immunoreactivity in the VMNvl, whereas no differences were detected in the mPOA, ARC or median eminence. Overall, the present findings indicate that TOP is coexpressed with ERalpha, and oestradiol regulates TOP expression in a brain region-specific manner in female mice, providing neuroanatomical evidence that TOP may function in reproductive physiology and/or behaviour.

Anesthetic management of labor in a patient with congenitally corrected transposition of the great arteries.

Laboring patients with congenitally corrected transposition of the great arteries present an interesting challenge to anesthesiologists because of the physiological changes that take place during pregnancy and the stress induced by labor. This paper describes the detailed management of a symptomatic parturient with congenitally corrected transposition of the great arteries. The patient was managed with epidural analgesia instituted early in labor with a continuous low-concentration infusion of local anesthetic and opioid but without an initial bolus. She underwent uneventful forceps-assisted vaginal delivery.

Lipase catalyse glycerolysis for kinetic resolution of racemates.

Candida antarctica lipase B catalyzed kinetic resolution of representative secondary alcohols, esters, and amine was successfully performed using triacetin or glycerol as solvents and acyl donor/acceptor. High conversions and enantioselectivities were achieved and the product was easily separated by simple extraction with diethyl ether.

Involvement of surface cysteines in activity and multimer formation of thimet oligopeptidase.

Thimet oligopeptidase is a metalloenzyme involved in regulating neuropeptide processing. Three cysteine residues (246, 248, 253) are known to be involved in thiol activation of the enzyme. In contrast to the wild-type enzyme, the triple mutant (C246S/C248S/C253S) displays increased activity in the absence of dithiothreitol. Dimers, purportedly formed through cysteines 246, 248 and 253, have been thought to be inactive. However, analysis of the triple mutant by native gel electrophoresis reveals the existence of dimers and multimers, implying that oligomer formation is mediated by other cysteines, probably on the surface, and that some of these forms are enzymatically active. Isolation and characterization of iodoacetate-modified monomers and dimers of the triple mutant revealed that, indeed, certain dimeric forms of the enzyme are still fully active, whereas others show reduced activity. Cysteine residues potentially involved in dimerization were identified by modeling of thimet oliogopeptidase to its homolog, neurolysin. Five mutants were constructed; all contained the triple mutation C246S/C248S/C253S and additional substitutions. Substitutions at C46 or C682 and C687 prevented multimer formation and inhibited dimer formation. The C46S mutant had enzymatic activity comparable to the parent triple mutant, whereas that of C682S/C687S was reduced. Thus, the location of intermolecular disulfide bonds, rather than their existence per se, is relevant to activity. Dimerization close to the N-terminus is detrimental to activity, whereas dimerization near the C-terminus has little effect. Altering disulfide bond formation is a potential regulatory factor in the cell owing to the varying oxidation states in subcellular compartments and the different compartmental locations and functions of the enzyme.

A novel applicator for low-dose-rate brachytherapy of gynecological cancers.

The standard low-dose-rate (LDR) delivery system utilized in the definitive management of patients with cervical carcinoma involves an intrauterine tandem and a pair of vaginal colpostats (ovoids). This well-known application system may deliver inadequate dosage if the tumor extends to the lower vaginal mucosa. During the gauze packing of the ovoids, either operator error or narrowing of the vaginal apex can result in mal-alignment of the colpostats and subsequent inadequate dosing to the ecto-cervix. A novel vaginal cylinder has been designed to address these concerns. Beginning January 1, 2001, patients with cancer of the cervix, endometrium, or vagina requiring LDR brachytherapy have been enrolled into an institutionally sanctioned clinical trial. As of May 31, 2001, a total of 11 patients have been entered but only 10 were successfully implanted with the test device. Patient follow-up has ranged from 0.81 years to 1.2 years (median: 0.96 years). Using our study applicator, all patients received within 10% of the preimplant prescribed dose to tumor. Also, no one had cumulative dosage that exceeded 10% of the maximum allowed dose to the critical normal tissues. Thus far, all study patients have had no clinical evidence of persistence/recurrence of disease or complications from treatment. The preliminary results presented herein clearly demonstrate the feasibility of this novel LDR vaginal cylinder in the treatment of a variety of clinical situations involving gynecological cancers. Our institutional trial is continuing.

Uniform binding of aminoacyl-tRNAs to elongation factor Tu by thermodynamic compensation.

Elongation factor Tu (EF-Tu) binds all elongator aminoacyl-transfer RNAs (aa-tRNAs) for delivery to the ribosome during protein synthesis. Here, we show that EF-Tu binds misacylated tRNAs over a much wider range of affinities than it binds the corresponding correctly acylated tRNAs, suggesting that the protein exhibits considerable specificity for both the amino acid side chain and the tRNA body. The thermodynamic contributions of the amino acid and the tRNA body to the overall binding affinity are independent of each other and compensate for one another when the tRNAs are correctly acylated. Because certain misacylated tRNAs bind EF-Tu significantly more strongly or weakly than cognate aa-tRNAs, EF-Tu may contribute to translational accuracy.

Use of plain radiography to screen for cervical spine injuries.

STUDY OBJECTIVE: Standard radiographic screening may fail to reveal any evidence of injury in some patients with spinal injury. The purposes of this investigation were to document the efficacy of standard radiographic views and to categorize the frequencies and types of injuries missed on plain radiographic screening of the cervical spine. METHODS: All patients with blunt trauma selected for radiographic cervical spine imaging at 21 participating institutions underwent a standard 3-view series (cross-table lateral, anteroposterior, and odontoid views), as well as any other imaging deemed necessary by their physicians. Injuries detected with screening radiography were then compared with final injury status for each patient, as determined by review of all radiographic studies. RESULTS: The study enrolled 34,069 patients with blunt trauma, including 818 patients (2.40% of all patients; 95% confidence interval [CI] 2.40% to 2.40%) having a total of 1,496 distinct cervical spine injuries. Plain radiographs revealed 932 injuries in 498 patients (1.46% of all patients; 95% CI 1.46% to 1.46%) but missed 564 injuries in 320 patients (0.94% of all patients; 95% CI 0.94% to 0.94%). The majority of missed injuries (436 injuries in 237 patients [representing 0.80% of all patients]; 95% CI 0.80% to 0.80%) occurred in cases in which plain radiographs were interpreted as abnormal (but not diagnostic of injury) or inadequate. However, 23 patients (0.07% of all patients; 95% CI 0.05% to 0.09%) had 35 injuries (including 3 potentially unstable injuries) that were not visualized on adequate plain film imaging. These patients represent 2.81% (95% CI 1.89% to 3.63%) of all injured patients with blunt trauma undergoing radiographic evaluation. CONCLUSION: Standard 3-view imaging provides reliable screening for most patients with blunt trauma. However, on rare occasions, such imaging may fail to detect significant unstable injuries. In addition, it is difficult to obtain adequate plain radiographic imaging in a substantial minority of patients.

Twice-daily prophylactic cranial irradiation for patients with limited disease small-cell lung cancer with complete response to chemotherapy and consolidative radiotherapy: report of a single institutional phase II trial.

Prophylactic cranial irradiation (PCI) has been demonstrated to significantly reduce the incidence of brain relapse from limited disease small-cell lung cancer (LD SCLC), but concerns about neurologic toxicity remain. The purpose of this report was to update a phase II institutional trial that explored the impact of twice-daily PCI on neurologic toxicity as well as outcome for this group of patients. All eligible subjects had documented complete response to induction chemotherapy and consolidative chest irradiation. The whole brain was treated with twice-daily fractions of 1.5 Gy with megavoltage irradiation to an approximate total dose of 30.0-36.0 Gy. Although not devised as a randomized study, approximately half of the eligible patients declined the protocol enrollment of their own volition and were retrospectively evaluated as a "historical" control group regarding the incidence of brain metastases. Fifteen patients accepted twice-daily PCI, with 12 deferring treatment. Median follow-up was 20 months. Disease-free survival at 2 years was 54% with twice-daily PCI versus 0% without any PCI (p = 0.013). Overall survival at 2 years was 62% with twice-daily PCI versus 23% without PCI (p = 0.032). No statistically significant neurologic deterioration was detected in the PCI group posttreatment. Thus, twice-daily PCI should be considered for patients with LD SCLC who achieve a complete response to chemoirradiation. A multi-institutional randomized trial would be necessary before making definitive recommendations.

A novel system consisting of Rh-DuPHOS and ionic liquid for asymmetric hydrogenations.

The ionic liquid [bmim][PF6] was found to provide extra stability to the air-sensitive chiral catalyst Rh-MeDuPHOS in asymmetric hydrogenation of enamides.

Clinician judgments of functional outcomes: how bias and perceived accuracy affect rating.

OBJECTIVE: To evaluate the accuracy of clinician judgments of patient function, the susceptibility of judges to bias, and the relation between a judge's degree of belief in his/her accuracy of classification to observed accuracy when using the FIM instrument. PARTICIPANTS: Fifty rehabilitation professionals. SETTING: 3 urban medical centers. DESIGN: Four randomized experiments among subjects to examine the effect of potentially biasing information on FIM ratings of patient vignettes. Participants answered 60 true/false questions regarding patient function and FIM score and indicated confidence in the accuracy of their answers. INTERVENTIONS: Manipulation of patient information. MAIN OUTCOME MEASURES: The standard FIM 7-point scale, observed proportion of correct responses to the 60 true/false questions, and a 6-category confidence scale for each of the 60 questions were used as dependent measures. RESULTS: FIM ratings assigned to others biased participants' FIM ratings of patient vignettes. Functional ability was overestimated when ratings in other domains were high and underestimated when they were low. Participants were overconfident in their ability to answer FIM questions accurately across all professional disciplines. CONCLUSION: Bias and poor judgment of level accuracy play a significant role in clinician ratings of patient functioning. Blind ratings and training in debiasing are potential solutions to the problem.

Planning recommendations for international emergency medicine and out-of-hospital care system development.

OBJECTIVES: To present suggestions on planning for development of emergency medicine (EM) and out-of-hospital care in countries that are in an early phase of this process, and to provide basic background information for planners not already familiar with EM. METHODS: The techniques and programs used by the authors and others in assisting in EM development in other countries to date are described. CONCLUSIONS: Some aspects of EM system development have applicability to most countries, but other aspects must be decided by planners based on country-specific factors. Because of the very recent initiation of many EM system development efforts in other countries, to the authors' knowledge there have not yet been extensive evaluative reports of the efficacy of these efforts. Further studies are needed on the relative effectiveness and cost-benefit of different EM development efforts.

Neuropeptidases regulating gonadal function.

The generation and metabolism of bioactive peptides involves a series of highly ordered proteolytic events. This post-translational processing can occur either within the cell, at the cell surface or after secretion. In the central nervous system a number of extracellular peptidases have been implicated in the regulated processing of peptides, particularly in the regulation of neuroendocrine function. The aim of this study has been to identify the peptidases involved in the metabolism of gonadotropin-releasing hormone (GnRH) and to characterize the factors and the mechanisms by which the activity of these peptidases are regulated. We have shown that both prolylendopeptidase and the thimet oligopeptidase EC 3.4. 24.15 are involved in GnRH metabolism and that both oestrogen and thiol-based reductants could be involved in the physiological regulation of their activities.

Validity of a set of clinical criteria to rule out injury to the cervical spine in patients with blunt trauma. National Emergency X-Radiography Utilization Study Group.

BACKGROUND: Because clinicians fear missing occult cervical-spine injuries, they obtain cervical radiographs for nearly all patients who present with blunt trauma. Previous research suggests that a set of clinical criteria (decision instrument) can identify patients who have an extremely low probability of injury and who consequently have no need for imaging studies. METHODS: We conducted a prospective, observational study of such a decision instrument at 21 centers across the United States. The decision instrument required patients to meet five criteria in order to be classified as having a low probability of injury: no midline cervical tenderness, no focal neurologic deficit, normal alertness, no intoxication, and no painful, distracting injury. We examined the performance of the decision rule in 34,069 patients who underwent radiography of the cervical spine after blunt trauma. RESULTS: The decision instrument identified all but 8 of the 818 patients who had cervical-spine injury (sensitivity, 99.0 percent [95 percent confidence interval, 98.0 to 99.6 percent]). The negative predictive value was 99.8 percent (95 percent confidence interval, 99.6 to 100 percent), the specificity was 12.9 percent, and the positive predictive value was 2.7 percent. Only two of the patients classified as unlikely to have an injury according to the decision instrument met the preset definition of a clinically significant injury (sensitivity, 99.6 percent [95 percent confidence interval, 98.6 to 100 percent]; negative predictive value, 99.9 percent [95 percent confidence interval, 99.8 to 100 percent]; specificity, 12.9 percent; positive predictive value, 1.9 percent), and only one of these two patients received surgical treatment. According to the results of assessment with the decision instrument, radiographic imaging could have been avoided in the cases of 4309 (12.6 percent) of the 34,069 evaluated patients. CONCLUSIONS: A simple decision instrument based on clinical criteria can help physicians to identify reliably the patients who need radiography of the cervical spine after blunt trauma. Application of this instrument could reduce the use of imaging in such patients.

Mapping contacts between Escherichia coli alanyl tRNA synthetase and 2' hydroxyls using a complete tRNA molecule.

A dual-specific derivative of yeast tRNA(Phe) is described whose features facilitate structure-function studies of tRNAs. This tRNA has been made in three different bimolecular forms that allow modifications to be easily introduced into any position within the molecule. A set of deoxynucleotide substituted versions of this tRNA has been created and used to examine contacts between tRNA and Escherichia coli alanyl-tRNA synthetase, an enzyme previously shown to interact with 2'-hydroxyls in the acceptor stem of the tRNA. Because the present experiments used a full-length tRNA, several contacts were identified that had not been previously found using microhelix substrates. Contacts at similar sites in the T-loop are seen in the cocrystal structure of tRNA(Ser) and Thermus thermophilus seryl-tRNA synthetase.

Radiation therapy for local control of eyelid sebaceous cell carcinoma: report of two cases and review of the literature.

PURPOSE: Because of previous reports of increased rate of recurrence and mortality after radiation therapy, eyelid sebaceous cell carcinoma has been considered radioresistant. Recent reports of success with primary radiation therapy have been attributed to advancements in irradiating technology and technique. Two cases of eyelid sebaceous cell carcinoma successfully treated with radiation therapy are reported. The techniques used are compared with the techniques described in previous reports, and factors favoring successful treatment are reevaluated. METHODS: Case series and review of the literature. Two cases of eyelid sebaceous cell carcinoma that underwent radiation therapy are described. Both patients were offered, but refused, surgical excision. One patient received 69 Gy combined superficial and megavoltage x-ray irradiation to the left lower eyelid. The second patient received 59 Gy megavoltage electron beam irradiation to the right upper eyelid. A review of the literature was performed, and Fisher's exact test analysis was used to compare the results of all reported cases treated with < or =55 Gy with those treated with >55 Gy. RESULTS: In both cases, the tumor responded to radiation therapy. One patient died 39 months after treatment, of myocardial infarction. The second patient is without clinical evidence of tumor recurrence 46 months after treatment. Fisher's exact test showed an advantage to patients treated with >55 Gy radiation (p = 0.05). CONCLUSION: Radiation therapy with an appropriate delivery system is effective as a curative treatment for eyelid sebaceous cell carcinoma when >55 Gy of radiation dose is delivered. It should be considered for patients seeking an alternative to surgical excision.