Structure of the human histone chaperone FACT Spt16 N-terminal domain.

The histone chaperone FACT plays an important role in facilitating nucleosome assembly and disassembly during transcription. FACT is a heterodimeric complex consisting of Spt16 and SSRP1. The N-terminal domain of Spt16 resembles an inactive aminopeptidase. How this domain contributes to the histone chaperone activity of FACT remains elusive. Here, the crystal structure of the N-terminal domain (NTD) of human Spt16 is reported at a resolution of 1.84 Å. The structure adopts an aminopeptidase-like fold similar to those of the Saccharomyces cerevisiae and Schizosaccharomyces pombe Spt16 NTDs. Isothermal titration calorimetry analyses show that human Spt16 NTD binds histones H3/H4 with low-micromolar affinity, suggesting that Spt16 NTD may contribute to histone binding in the FACT complex. Surface-residue conservation and electrostatic analysis reveal a conserved acidic patch that may be involved in histone binding.

A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators.

PURPOSE: To determine whether early goal-directed therapy (EGDT) reduces mortality compared with other resuscitation strategies for patients presenting to the emergency department (ED) with septic shock. METHODS: Using a search strategy of PubMed, EmBase and CENTRAL, we selected all relevant randomised clinical trials published from January 2000 to January 2015. We translated non-English papers and contacted authors as necessary. Our primary analysis generated a pooled odds ratio (OR) from a fixed-effect model. Sensitivity analyses explored the effect of including non-ED studies, adjusting for study quality, and conducting a random-effects model. Secondary outcomes included organ support and hospital and ICU length of stay. RESULTS: From 2395 initially eligible abstracts, five randomised clinical trials (n = 4735 patients) met all criteria and generally scored high for quality except for lack of blinding. There was no effect on the primary mortality outcome (EGDT: 23.2% [495/2134] versus control: 22.4% [582/2601]; pooled OR 1.01 [95% CI 0.88-1.16], P = 0.9, with heterogeneity [I(2) = 57%; P = 0.055]). The pooled estimate of 90-day mortality from the three recent multicentre studies (n = 4063) also showed no difference [pooled OR 0.99 (95% CI 0.86-1.15), P = 0.93] with no heterogeneity (I(2) = 0.0%; P = 0.97). EGDT increased vasopressor use (OR 1.25 [95% CI 1.10-1.41]; P < 0.001) and ICU admission [OR 2.19 (95% CI 1.82-2.65); P < 0.001]. Including six non-ED randomised trials increased heterogeneity (I(2) = 71%; P < 0.001) but did not change overall results [pooled OR 0.94 (95% CI 0.82 to 1.07); P = 0.33]. CONCLUSION: EGDT is not superior to usual care for ED patients with septic shock but is associated with increased utilisation of ICU resources.

Ministry of health clinical practice guidelines: cancer screening.

The Ministry of Health publishes national clinical practice guidelines to provide doctors and patients in Singapore with evidence-based guidance on managing important medical conditions. This article reproduces the introduction and executive summary (with key recommendations from the guidelines) from the Ministry of Health clinical practice guidelines on cancer screening, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website (http://www.moh.gov. sg/mohcorp/publications.aspx?id=24018). The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

After-hour home care service provided by a hospice in Singapore.

A home care Hospice programme was set up to provide care to the patients with advanced diseases and their families in Singapore. After office-hour, the service is managed by a doctor on weekdays, with the assistance of a nurse during daytime on Saturdays, Sundays and public holidays. The doctor on-call made an average of 3.1 phone calls and 1.3 visits each weekday evening. Over the weekends and public holidays, there were a mean of 16.7 phone calls and 6 visits each day. More than half of the visits (50.3%) were made for certification of death. The commonest symptoms that prompted visits were dyspnoea (20%) and pain (12.2%). The busiest period during weekdays was between 6.00 pm and 11.00 pm, when our doctors did most of their visits. The workload of the hospice home care service is likely to increase and resources such as family health physicians can be explored to help to meet this increasing demand. This can be achieved through the provision of comprehensive training and easy accessibility to medical records which are kept with patients.

Molecular enhancement of porcine cardiac chronotropy.

OBJECTIVE: To test the potential of gene transfer approaches to enhance cardiac chronotropy in a porcine system as a model of the human heart. METHODS: Plasmids encoding either the human beta(2) adrenergic receptor or control constructs were injected into the right atria of native Yorkshire pig hearts. Percutaneous electrophysiological recording catheters equipped with 33 gauge circular injection needles were positioned in the mid-lateral right atrium. At the site of the earliest atrial potential the circular injection needles were rotated into the myocardium and the beta(2) adrenergic receptor (n = 6) or control plasmid constructs (n = 5) were injected. RESULTS: Injection of the beta(2) adrenergic receptor construct significantly enhanced chronotropy compared with control injections. The average (SD) heart rate of the pigs was 108 (16) beats/min before injection. Two days after injection with control plasmids the heart rate was 127 (25) beats/min (NS compared with preinjection rates). After injection with plasmid encoding the beta(2) adrenergic receptor the heart rate increased by 50% to 163 (33) beats/min (p < 0.05 compared with preinjection and postinjection control rates). CONCLUSIONS: The present studies showed in a large animal model that local targeting of gene expression may be a feasible modality to regulate cardiac pacemaking activity. In addition, these investigations provide an experimental basis for developing future clinical gene transfer approaches to upregulate heart rate and modulate cardiac conduction.

Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.

Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Two identified lissencephaly genes do not account for all known cases, and additional lissencephaly syndromes have been described. An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN). The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity. RELN encodes a large (388 kD) secreted protein that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11 ), alpha3beta1 integrin and protocadherins. Although reelin was previously thought to function exclusively in brain, some humans with RELN mutations show abnormal neuromuscular connectivity and congenital lymphoedema, suggesting previously unsuspected functions for reelin in and outside of the brain.

Concomitant boost radiation therapy for inoperable non-small-cell lung cancer: preliminary report of a prospective randomized study.

PURPOSE: The radiation therapy results for patients with inoperable non-small-cell lung cancer (NSCLC) have been disappointing. Tumor dose escalation using concomitant boost technique (CBT) has been shown to improve local control in a few prospective studies. This trial was carried out to prospectively assess the radiation response and acute toxicity of CBT in comparison to the conventional treatment technique (CTT). METHODS AND MATERIALS: Ninety-seven consecutive eligible patients were entered in this prospective clinical trial between November 1994 and February 1998. Patients were randomized to receive either CBT (43 patients) or CTT (54 patients) radiation therapy. These patients either refused chemotherapy or were judged as unsuitable for chemotherapy. Patients in the CBT group received 46.8 Gy in 26 fractions using large fields that encompassed the gross and occult disease. A concomitant boost of 18.2 Gy (0.7 Gy per fraction) was delivered to the gross disease using small fields with 1.5-cm margins. The small fields were treated concurrently with the large fields and the total dose to the tumor area was 65 Gy in 26 fractions. Patients in the CTT group received 70.8 Gy in 38 fractions. The acute toxicity between each group was compared. The response rate was analyzed and compared by treatment group, gender, age, stage, histology, initial Karnofsky performance score (KPS), severity of acute toxicity, and maximum body weight loss (MBWL) during treatment course. RESULTS: The demographic parameters such as sex, age, and stage were evenly distributed in each treatment group. The majority of these patients had Stage IIIA and IIIB disease. Overall median treatment times were 39 days for the CBT group of patients and 62 days for the CTT group. No treatment-related mortality was found. There were 2 patients in the CTT group with acute RTOG Grade 3 lung toxicity, and no Grade 3 lung or esophageal toxicity was observed in CBT group. The response rates, assessed by radiographic images, were 69.8% and 48.1% for the CBT and CTT patients, respectively. Univariate and multivariate analysis revealed that patients in the CBT group, patients with better KPS, and patients with more severe acute toxicity had a higher response rate. CONCLUSION: This study demonstrates that concomitant boost radiation therapy is tolerable, and produces a superior response rate than conventional radiation therapy for patients with inoperable NSCLC. The length of treatment was reduced from 38 to 26 treatment days, almost a 30% reduction.

Y2K: effects on pacemaker and implantable defibrillator programmers.

All permanent pacemakers and implantable defibrillators (PPM/ICDs) will continue to function as programmed without regard to the date in the year 2000 (Y2K). All manufacturers contacted reassured us that some of these devices incorporate a day/year clock in the circuitry; however, these are not involved in sensing or delivering programmed therapy. Some manufacturers' device programmers will roll over to the year 2000 without any problems at all, whereas others may have difficulty with date and time stamping on printed reports. We tested 14 different types of PPM/ICD programmers for Y2K compliance using 8 tests. Five of the 14 models passed each test and were labeled at our institution with a green "Y2K" sticker to identify them as Y2K compatible and needing no special attention after December 31, 1999. The most common test failed was the ability to roll the date forward from December 31, 1999, with the programmer power off. Organizations should consider testing and replacing noncompliant device programmers or placing a red sticker with "Y2K" crossed out on noncompliant pieces. The red sticker alerts the advanced practice nurse or physician to the need to confirm the appropriate date and time in the programmer after startup in the year 2000 and before interrogating or programming any PPM/ICD, to avoid inappropriate date and time stamping on printed reports from that programmer.

Ectopic orbital meningioma: a case report and review.

PURPOSE: To describe a well-documented case of ectopic orbital meningioma, to review the literature on the subject, and to recommend treatment. METHODS: Neuroradiologic investigations were suggestive of orbital meningioma. The patient underwent total excision of the mass, which was subsequently examined by light microscopy and immunohistochemistry. RESULTS: The patient was diagnosed with ectopic orbital meningioma which was locally invasive. The tumor was surgically excised, and did not recur during a 42-month follow-up interval. CONCLUSIONS: Ectopic orbital meningiomas are rare tumors that develop from ectopic arachnoid tissue. Although locally invasive, the prognosis is favorable if the tumor is completely removed.

Divalent metal derivatives of the hamster dihydroorotase domain.

Dihydroorotase (DHOase, EC 3.5.2.3) is a zinc enzyme that catalyzes the reversible cyclization of N-carbamyl-L-aspartate to L-dihydroorotate in the third reaction of the de novo pathway for biosynthesis of pyrimidine nucleotides. The recombinant hamster DHOase domain from the trifunctional protein, CAD, was overexpressed in Escherichia coli and purified. The DHOase domain contained one bound zinc atom at the active site which was removed by dialysis against the chelator, pyridine-2,6-dicarboxylate, at pH 6.0. The apoenzyme was reconstituted with different divalent cations at pH 7.4. Co(II)-, Zn(II)-, Mn(II)-, and Cd(II)-substituted DHOases had enzymic activity, but replacement with Ni(2+), Cu(2+), Mg(2+), or Ca(2+) ions did not restore activity. Atomic absorption spectroscopy showed binding of one Co(II), Zn(II), Mn(II), Cd(II), Ni(II), or Cu(II) to the enzyme, while Mg(II) and Ca(II) were not bound. The maximal enzymic activities of the active, reconstituted DHOases were in the following order: Co(II) --> Zn(II) --> Mn(II) --> Cd(II). These metal substitutions had major effects upon values for V(max); effects upon the corresponding K(m) values were less pronounced. The pK(a) values of the Co(II)-, Mn(II)-, and Cd(II)-substituted enzymes derived from pH-rate profiles are similar to that of Zn(II)-DHOase, indicating that the derived pK(a) value of 6.56 obtained for Zn-DHOase is not due to ionization of an enzyme-metal aquo complex, but probably a histidine residue at the active site. The visible spectrum of Co(II)-substituted DHOase exhibits maxima at 520 and 570 nm with molar extinction coefficients of 195 and 210 M(-1) cm(-1), consistent with pentacoordination of Co(II) at the active site. The spectra at high and low pH are different, suggesting that the environment of the metal binding site is different at these pHs where the reverse and forward reactions, respectively, are favored.

Synthesis and enzymic evaluation of 4-mercapto-6-oxo-1, 4-azaphosphinane-2-carboxylic acid 4-oxide as an inhibitor of mammalian dihydroorotase.

The design, synthesis, and enzymic evaluation of cis- and trans-4-mercapto-6-oxo-1,4-azaphosphinane-2-carboxylic acid 4-oxide 5 against mammalian dihydroorotase is presented. The design strategy for 5 was based on the strong affinity of phosphinothioic acids for zinc and that 5 also resembles the postulated tetrahedral transition state for the enzyme-catalyzed reaction. The synthesis of 5 utilized a novel protection/deprotection sequence upon 4-hydroxy-6-oxo-1, 4-azaphosphinane-2-carboxylic acid 4-oxide 4, followed by incorporation of alpha-phenyl benzenemethanethiol and exhaustive deprotection to afford 5 in 40% overall yield from 4. The activities of both isomers of 5 as inhibitors of mammalian dihydroorotase were marginally greater than that of the parent phosphinic acid 4, indicating a weak binding enhancement due to the phosphinothioic acid moiety.

Hybrid pharmacologic and ablative therapy: a novel and effective approach for the management of atrial fibrillation.

INTRODUCTION: Maintenance of sinus rhythm in patients with recurrent atrial fibrillation is often difficult to achieve with pharmacologic therapy. Complex catheter ablative procedures are being developed, but efficacy and safety issues remain to be clarified. We hypothesized that combined pharmacologic and simple ablative therapies in a targeted subset of patients will improve success in the treatment of atrial fibrillation. METHODS AND RESULTS: We identified 13 patients (mean age 61.5 +/- 16.2 years) with atrial fibrillation who converted to electrocardiographic atrial flutter during antiarrhythmic drug treatment. Surface ECG suggested "typical" atrial flutter in 11 patients and "atypical" atrial flutter in 2. Intracardiac mapping and entrainment studies revealed 9 patients had counterclockwise isthmus-dependent atrial flutter, and the remaining 4 had complex activation patterns, suggesting the presence of multiple wavefronts. All 9 patients with typical atrial flutter underwent successful ablation. None of the 4 patients with complex activation patterns had successful ablation. Patients were followed for recurrences of atrial arrhythmias via clinic visits, record review, and interviews. In patients who underwent successful ablation and continued on antiarrhythmic drugs, 88.9% remain in sinus rhythm after a mean follow-up of 14.3 +/- 6.9 months (range 1 to 28). CONCLUSION: In patients who experience conversion of atrial fibrillation to atrial flutter during antiarrhythmic drug treatment, ablation and continuation of pharmacologic therapy is a safe and effective means of achieving and maintaining sinus rhythm.

Regulated expression of cadherin-11 in human extravillous cytotrophoblasts undergoing aggregation and fusion in response to transforming growth factor beta 1.

Transforming growth factor beta 1 is believed to be a key regulator of extravillous cytotrophoblast invasion during the first trimester of pregnancy. In addition, this growth factor has been shown to regulate cellular differentiation and fusion in cultured extravillous cytotrophoblasts. To date, the cellular mechanisms by which transforming growth factor beta 1 promotes these developmental processes remain poorly understood. Recent studies indicate that the expression of the novel cadherin subtype, known as cadherin-11, is associated with the terminal differentiation and fusion of villous cytotrophoblasts isolated from the human term placenta and human myoblasts in vitro. In this study, cadherin-11 mRNA and protein expression were examined in primary cultures of human extravillous cytotrophoblasts cultured in the presence of increasing concentrations of transforming growth factor beta 1 using northern and western blot analysis, respectively. Transforming growth factor beta 1 was shown to increase cadherin-11 mRNA and protein expression in these cultured extravillous cytotrophoblasts in a dose-dependent manner. Cadherin-11 was further localized to the large cellular aggregates and multinucleated cells that formed in response to increasing concentrations of transforming growth factor beta 1 using immunocytochemistry. Collectively, these observations suggest that the morphogenetic effects of transforming growth factor beta 1 on cultured extravillous cytotrophoblasts are mediated, at least in part, by an increase in cadherin-11 expression. This study not only adds to the understanding of the cellular mechanisms by which transforming growth factor beta 1 promotes trophoblast differentiation and fusion but provides useful insight into the cell biology of the cadherins.

Combined-modality therapy for squamous carcinoma of the buccal mucosa: treatment results and prognostic factors.

BACKGROUND: Reports on locoregional control and survival of squamous cell carcinoma of buccal mucosa are scarce in literature. In this study, a single institutions's experience of combined surgery and postoperative radiotherapy (RT) for buccal mucosal malignancy with favorable results was analyzed and presented. The prognostic factors on locoregional control were also discussed. METHODS: From January 1988 to July 1994, 57 patients with squamous cell carcinoma of buccal mucosa treated by surgery and RT were reviewed. The distributions according to American Joint Committee on Cancer (AJCC) staging were: stage II, 6; stage III, 21; and stage IV, 30 patients. Total dose of RT at the buccal area ranged from 45 Gy to 68.4 Gy, median 61.2 Gy. Tumor-related factors (AJCC stage, T stage, histologic grading, pathologic tumor invasion to skin of cheek, adjacent bony structures, and regional lymph nodes) and treatment-related factors (surgical margin, radiation dose, and the time interval between operation and RT) were analyzed to determine their influence on locoregional control. RESULTS: Three-year actuarial locoregional control rate, overall survival rate, and disease-specific survival rates were 64%, 55%, and 62%, respectively. Ten of these 22 patients (45%) with recurrent tumors were reoperated, but only 2 patients were successfully salvaged. Positive surgical margin and tumor invasion to skin of cheek were significantly poor prognostic factors on locoregional control by univariate analysis. In multivariate analysis, tumor invasion to skin of cheek was the only prognostic factor (p = .0014). CONCLUSIONS: Locoregional failure was the major cause of death for squamous buccal mucosa cancers managed with surgery and RT. Few recurrences could be detected early and successfully salvaged. Skin of cheek involvement is an important prognostic factor for buccal mucosa cancers.

The biological effectiveness of intermittent irradiation as a function of overall treatment time: development of correction factors for linac-based stereotactic radiotherapy.

PURPOSE: Continuous irradiation of relatively short duration as administered in gamma-ray stereotactic radiosurgery (SRS) is biologically not equivalent to the more protracted intermittent exposures during accelerator-based radiosurgery with multiple arcs. Accelerator-based SRS and fractionated stereotactic radiotherapy (SRT) is currently performed with a high degree of variability in equipment and techniques resulting in highly variable treatment delivery times. The present work is designed to quantify the effects of radiation delivery times on biological effectiveness. For this, the intermittent radiation delivery schemes, typical for linac-based SRS/SRT, have been simulated in vitro to derive biological correction factors. METHODS AND MATERIALS: The experiments were carried out using U-87MG human glioma cells in suspension at 37 degrees C irradiated with 6 MV X-rays to clinically relevant doses ranging from 6 to 18 Gy, delivered over total irradiation times from 16 min to 3 h. The resulting cell survival data was used to calculate dose correction factors to compensate for wide variations in dose delivery times. RESULTS: At each total dose level, cell survival increased with increasing total irradiation time. The increase in survival was more pronounced at higher dose levels. At a total dose of 12 Gy, cell survival increased by a factor of 4.7 when irradiation time was increased from 16 to 112 min. Dose correction factors were calculated to allow biologically equivalent irradiations over the range of exposure times. Cells irradiated with corrected total doses of 11.5 Gy delivered incrementally in 16 min up to 13.3 Gy in 112 min were found to exhibit the same survival within the experimental limits of accuracy. CONCLUSIONS: For a given total dose, variations in dose delivery time typical of SRS/SRT techniques will result in significant changes in cell survival. In the dose range studied, an isoeffect dose correction factor of 2 to 3 cGy/min was shown to compensate for the change in delivery time for U-87 MG human gloma cells in vitro.

Electron/photon matched field technique for treatment of orbital disease.

PURPOSE: A number of approaches have been described in the literature for irradiation of malignant and benign diseases of the orbit. Techniques described to date do not deliver a homogeneous dose to the orbital contents while sparing the cornea and lens of excessive dose. This is a result of the geometry encountered in this region and the fact that the target volume, which includes the periorbital and retroorbital tissues but excludes the cornea, anterior chamber, and lens, cannot be readily accommodated by photon beams alone. To improve the dose distribution for these treatments, we have developed a technique that combines a low-energy electron field carefully matched with modified photon fields to achieve acceptable dose coverage and uniformity. METHODS AND MATERIALS: An anterior electron field and a lateral photon field setup is used to encompass the target volume. Modification of these fields permits accurate matching as well as conformation of the dose distribution to the orbit. A flat-surfaced wax compensator assures uniform electron penetration across the field, and a sunken lead alloy eye block prevents excessive dose to the central structures of the anterior segment. The anterior edge of the photon field is modified by broadening the penumbra using a form of pseudodynamic collimation. Direct measurements using film and ion chamber dosimetry were used to study the characteristics of the fall-off region of the electron field and the penumbra of the photon fields. From the data collected, the technique for accurate field matching and dose uniformity was generated. RESULTS: The isodose curves produced with this treatment technique demonstrate homogeneous dose coverage of the orbit, including the paralenticular region, and sufficient dose sparing of the anterior segment. The posterior lens accumulates less than 40% of the prescribed dose, and the lateral aspect of the lens receives less than 30%. A dose variation in the match region of +/-12% is confronted when an unmodified photon field edge is matched with the fall-off of the electron field at the 50% isodose lines. By modifying the penumbra, the dose variation is reduced to +/-2%. Treatment setup accuracy is essential. CONCLUSIONS: The electron/photon matched field technique offers a uniform isodose distribution for treatment of the orbit that has not been previously achieved. With this technique a homogeneous dose can be delivered to the entire orbit while avoiding a significant dose to the anterior segment and minimizing the risk of morbidity.

Deformation-induced hierarchical flows and drag forces in bone canaliculi and matrix microporosity.

Existing theories for interstitial flows in bone have only examined the contributions from different flow systems separately, such as the flows through the microporosity, the canaliculi, and the Haversian canals. An overall model encompassing the hierarchical microstructure is important to our understanding of the actual physics of flows in bone. The flow-induced drag forces and streaming electrical potentials could interact with the osteocytes to effect biological responses. A finite element model was developed to study the contributions from various hierarchical flow channels in bone. Cortical bone is modelled as a fully hydrated biphasic poroelastic material with a superposing network of one-dimensional channels radiating from the Haversian canals representing the canaliculi. Interfacial cross-flows between these one-dimensional channels and the neighbouring poroelastic matrix are driven by the pressure differences between the matrix and the channel. The model was subjected to stress fields simulating uniform compression and pure bending. The effects of the interfacial permeability and the solid content within the channels on the drag forces in the channels were assessed. Abrupt changes in these drag forces occurred as the channel solidity approached that of the microporosity. The results were quite sensitive to the interfacial permeability, i.e. the interconnectivity between the canalicular system and the matrix microporosity. This biomechanical model should be useful to the study of mechanotransduction in bone.

A retrospective quality of life analysis using the Lung Cancer Symptom Scale in patients treated with palliative radiotherapy for advanced nonsmall cell lung cancer.

PURPOSE: To measure symptom palliation in patients treated with radiation therapy for advanced nonsmall cell lung cancer (NSCLC). METHODS AND MATERIALS: Five hundred thirty patients with NSCLC were treated at the Medical College of Virginia between 1988 and 1993. Sixty-three patients with the least favorable prognostic features received palliative radiation to 30 Gy in 10 or 12 fractions for symptoms related to the presence of intrathoracic tumor. The observer portion of the Lung Cancer Symptom Scale (LCSS) was employed in a retrospective chart review, scoring measures of appetite, fatigue, cough, dyspnea, hemoptysis, and pain. RESULTS: In 54 evaluable patients, median survival was 4 months and was independent of age, stage, performance status, or histology. Ninety-six percent of the patients had at least one LCSS symptom at presentation. Fatigue was unaffected by therapy. Improvements in appetite (p = 0.68) and pain (p = 0.61) were not statistically significant. There was, however, a statistically significant reduction in cough (p = 0.01), hemoptysis (p = 0.001), and dyspnea (p = 0.0003). Self-limiting acute side effects included transient esophagitis in 37% of patients, though no severe toxicities were noted. CONCLUSIONS: These results suggest symptomatic benefit from radiotherapy even in those NSCLC patients with advanced disease and a limited life expectancy. Treatment should be given to patients whose symptoms are most amenable to palliation. A site-specific quality of life instrument such as the LCSS should be included within any future clinical trial of NSCLC management so that symptom control may be scored as a treatment outcome in addition to disease-free survival.

Activation and repolarization patterns are governed by different structural characteristics of ventricular myocardium: experimental study with voltage-sensitive dyes and numerical simulations.

INTRODUCTION: Substantial progress has been made in our understanding of transmural activation across ventricular muscle through studies of excitation patterns and potential distributions. In contrast, repolarization sequences are poorly understood because of experimental difficulties in mapping action potential durations (APDs) using extracellular electrodes. METHODS AND RESULTS: Langendorff-perfused guinea pig hearts and isolated coronary-perfused left ventricular sheet preparations were stained with the voltage-sensitive dye RH-421 and optical APs were recorded with a photodiode array. Epicardial maps were constructed using a triangulation method applied to matrices of activation and repolarization times determined from (dF/dt)max and (d2F/dt2)max' respectively. Numerical simulations were carried out based on: (1) a modified Luo-Rudy model; (2) the three-dimensional architecture of ventricular fibers; and (3) the intrinsic spatial distribution of APDs. In ventricular sheets, epicardial stimulation elicited elliptical activation patterns with the major axis aligned with the longitudinal axis of epicardial fibers. When the pacing electrode was progressively inserted from epicardium to endocardium, the major axes rotated gradually, clockwise by 45 degrees, and the eccentricity decreased from 2 to 1.14. Repolarization showed a relatively uniform pattern, independent of pacing site, beginning at the apex and spreading to the base. CONCLUSION: In experiments and simulations, the helical rotation of epicardial excitation isochrones caused by pacing at increasing depth in the myocardium correlated with the helical three-dimensional architecture of ventricular fibers. In contrast, repolarization was independent of the activation sequence and was mainly guided by spatial differences in APDs between apex and base.

Radiation alone for carcinoma of the vagina: variation in response related to the location of the primary tumor.

BACKGROUND: A retrospective study of 40 patients with histologically confirmed carcinoma of the vagina is reported. The patients were treated by radiation alone (a combination of external beam therapy and implants) between October 1969 and September 1991 at the Medical College of Virginia Hospital in Richmond. METHODS: Thirty-three patients (82%) had squamous cell carcinoma, 2 patients (7%) had adenocarcinoma, and 2 patients (5%) had poorly differentiated cancers (1 melanoma and 1 leiomyosarcoma). The patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system; there were 13 patients (33%) in Stage 1, 21 (52%) in Stage II, 4 (10%) in Stage III, and 2 (5%) in Stage IV. Thirty-six patients (90%) were treated with external beam therapy and some combination of implant: cylinder, ovoid, or interstitial implants with iodine-125 or iridium-192 (afterloading). Only 4 patients (10%) received treatment by implant only. RESULTS: Based on their response, two groups of patients were identified. Group I had 23 patients with tumors predominantly located in the proximal half of the vagina; there were 8 patients in Stage I, 11 in Stage II, 3 in Stage III, and 1 in Stage IV. Of these, three patients failed: one each in Stages III and IV and one Stage II patient was salvaged by surgery. Three patients died due to unrelated causes but with local control. The 5-year actuarial survival in this group was 81%. Group II had 17 patients with tumors located in the mid to distal half of the vagina; there were 5 patients in Stage I, 10 in Stage II, and 2 in Stage IV. Ten patients failed. Eight patients in Stage II had persistent disease, were lost to follow-up, and are presumed dead. Two patients with Stage IV disease also had inadequate local control. The overall actuarial survival in the distal group was 41%, which was significantly worse than the proximal group (81%), at a P value of 0.05. CONCLUSIONS: This study discusses the curability of carcinoma of the vagina based on its anatomic location when predominantly similar treatment techniques and radiation doses were applied to either the proximal or the distal part of the vagina, those with cancer in the proximal half had better survival (81%) than those whose cancer was in the distal half (41%).