Topological classification and enumeration of RNA structures by genus.

To an RNA pseudoknot structure is naturally associated a topological surface, which has its associated genus, and structures can thus be classified by the genus. Based on earlier work of Harer-Zagier, we compute the generating function Dg,σ (z) = ∑n dg,σ (n)zn for the number dg,σ (n) of those structures of fixed genus g and minimum stack size σ with n nucleotides so that no two consecutive nucleotides are basepaired and show that Dg,σ (z) is algebraic. In particular, we prove that dg,2(n) ∼ kg n3(g−1/2 )γ n2, where γ2 ≈ 1.9685. Thus, for stack size at least two, the genus only enters through the sub-exponential factor, and the slow growth rate compared to the number of RNA molecules implies the existence of neutral networks of distinct molecules with the same structure of any genus. Certain RNA structures called shapes are shown to be in natural one-to-one correspondence with the cells in the Penner-Strebel decomposition of Riemann's moduli space of a surface of genus g with one boundary component, thus providing a link between RNA enumerative problems and the geometry of Riemann's moduli space.

Hospital-treated psychosis and suicide in a rural community (1877-2005). Part 1: Incidence rates.

OBJECTIVE: To calculate the incidence rates of hospital-treated psychosis and suicide in historical cohorts of a small rural community in southeast Norway, and to compare the local findings with the national ones. METHOD: We have carried out a longitudinal epidemiological study, reviewing the patient records at the mental hospitals of people born in the rural community after 1845. Based on these records, we have constructed a local register of psychosis and suicide in this population. The local incidence rates of psychosis and suicide have been compared with the national ones. RESULTS: The overall local incidence rates of psychosis and suicide were similar to the national ones. The local rates of schizophrenia dropped considerably after World War II. CONCLUSION: The overall local incidence rates of psychosis and suicide seem to be representative for the country at large despite frequent endogamy. The recent drop in the incidence rate of schizophrenia seems to be in agreement with several international studies.

Hospital-treated psychosis and suicide in a rural community (1877-2005). Part 2: Genetic founder effects.

OBJECTIVE: To demonstrate the existence of genetic founder effects in hospital-treated cases of psychosis and self-harm in historical cohorts of a small rural population. METHOD: These cohorts consist of named persons born after 1845. The cumulative case registers were linked to the purported pedigrees of three presumed mentally ill founders living in the community in the 17th and 18th centuries. We compared the incidence of psychosis and self-harm in the genetically unexposed population and in three exposed founder populations. RESULTS: We found a preponderance of organic mental disorders and schizophrenia in the twice-exposed founder population and of other non-organic psychosis and self-harm in the thrice-exposed founder population. CONCLUSION: The genetic impact of the founders seems to have affected the incidence rates of severe psychiatric disorders of their descendants in two ways. A founder effect is detected in organic mental disorders and schizophrenia, and it seems to run independently of that detected in affective psychotic disorders and intentional self-harm.

Within- and across-person uniformity of body condition scoring in Danish Holstein cattle.

Body condition scores (BCS) are very useful for dairy herd management and breeding programs, but the consistency and quality of recordings made by consultants in the field are unknown. The objectives of this study were 1) to estimate the agreement in BCS within and among practicing dairy veterinarians and 2) to provide an indication of the effects of training and the value of calibration, and of what efforts need to be made to obtain a validity and precision in BCS adequate for management purposes. A total of 2,230 scores were recorded by 51 practicing dairy veterinarians and 6 highly trained instructors. The 6 instructors were cross-trained to validate calibration consistency in assigning BCS. Each individual scored approximately 20 cows twice, with the second scoring occurring approximately 2.5 h after the first. Between the 2 recordings, the respective instructors conducted a training session for the practicing veterinarians using other cows. A weighted kappa coefficient was used to assess agreement among and within classifiers. Excellent agreement (kappa > or = 0.86) was documented between repeated BCS recorded for the same cows by the highly trained instructors. In addition, the BCS provided by multiple classifiers from the instructor team appeared to be comparable across herds and classifiers. This legitimizes the use of BCS for benchmarking at both the cow and the herd level. The within-classifier and between-classifier kappa values were in the ranges of 0.22 to 0.75 and 0.17 to 0.78, respectively, in the group of practicing dairy veterinarians. Many of the veterinarians provided estimates of average BCS that differed considerably from the BCS recorded by the instructors. Between-classifier comparisons of herd BCS are not warranted unless a validation has been performed. If scores are collected by multiple classifiers with varying experience, a valid but imprecise estimate of the true population mean of BCS may be obtained if classifiers are inexperienced. The limited training effort used in this study seemed to have brought about substantial improvement in the validity and precision of the BCS determined by practicing veterinarians, compared with the BCS recorded on the same cows by highly trained classifiers.

On the possibility to improve the performance of flow injection analysis by deconvolution of spectrophotometric data.

The concentration profile of chemical species pumped through a tubular system of 0.5-mm inner diameter is found to be trapezial shaped, as described theoretically by including the spatial resolution of the instrument, friction and diffusion. By applying the theory, which is based on the concept of segment flow, to experiments, it is shown that an injected segment of solute is diluted predominantly at the front and at the tail proportion of the segment in motion. A double-peaked structure in experiments of flow-injection analysis (FIA) was identified and by including all the data of the experimentally measured responses, it was possible to obtain an improvement of the sensitivity by a factor of 22 and obtain almost a factor of three times improvement on the standard deviation.

Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.

BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

An approach to long-range electron transfer mechanisms in metalloproteins: in situ scanning tunneling microscopy with submolecular resolution.

In situ scanning tunneling microscopy (STM) of redox molecules, in aqueous solution, shows interesting analogies and differences compared with interfacial electrochemical electron transfer (ET) and ET in homogeneous solution. This is because the redox level represents a deep indentation in the tunnel barrier, with possible temporary electronic population. Particular perspectives are that both the bias voltage and the overvoltage relative to a reference electrode can be controlled, reflected in spectroscopic features when the potential variation brings the redox level to cross the Fermi levels of the substrate and tip. The blue copper protein azurin adsorbs on gold(111) via a surface disulfide group. Well resolved in situ STM images show arrays of molecules on the triangular gold(111) terraces. This points to the feasibility of in situ STM of redox metalloproteins directly in their natural aqueous medium. Each structure also shows a central brighter contrast in the constant current mode, indicative of 2- to 4-fold current enhancement compared with the peripheral parts. This supports the notion of tunneling via the redox level of the copper atom and of in situ STM as a new approach to long-range electron tunneling in metalloproteins.

[Patients with early stages of endometrial cancer should be spared adjuvant radiotherapy. Danish Endometrial Cancer Group]. / Patienter med tidlige stadier af endometriecancer bør skånes for adjuverende strålebehandling.

In an attempt to create uniform nationwide guidelines for the management of all stages of endometrial carcinoma, and to limit the use of adjuvant radiation therapy in stage I disease to high-risk patients only, a protocol was developed by the Danish Endometrial Cancer group (DEMCA). From September 1986 through August 1988, 1214 women in Denmark with newly diagnosed carcinoma of the endometrium have been treated according to this protocol. This figure represents all endometrial carcinomas diagnosed in Denmark during this two-year period. The primary treatment was total abdominal hysterectomy and bilateral salpingo-oophorectomy, no preoperative radiation therapy was delivered. In 1039 cases no macroscopic residual tumour and/or microscopic tumor tissue in the resection margins was found following surgery. Based on surgery and histopathology, these patients were classified as: P-stage I low risk (n = 641), P-stage I high risk (n = 235), P-stage II (n = 105) and P-stage III, Group 1 (n = 58). No postoperative radiation therapy was given to P-I low risk cases. P-I high risk, P-II, and P-III (Group 1) cases received external radiation therapy. Recurrence rate at 68-92 months follow-up was 45/641 (7%) in P-I low risk, 36/235 (15%) in P-I high risk, 30/105 (29%) in P-II, and 27/58 (47%) in P-III (Group 1) cases. Fifteen of 17 vaginal recurrences in P-I low risk cases were salvaged (mean observation time 61 months). In this population-based investigation it has been shown that P-stage low-risk patients are adequately treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy, and that no pre- or postoperative radiation therapy is necessary.

Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study.

PURPOSE: To elucidate the effect of a doubled carboplatin dose-intensity in epithelial ovarian cancer in combination with a fixed dose of cyclophosphamide. PATIENTS AND METHODS: A total of 222 patients with epithelial ovarian cancer stages II to IV were included in the study. Following surgery, patients were randomly assigned to receive carboplatin at an area under the concentration-versus-time curve (AUC) of 4 (AUC4) or carboplatin at an AUC of 8 (AUC8) and cyclophosphamide 500 mg/m2 given every 4 weeks for six courses. The AUC was calculated according to Calvert's formula. In 123 patients, the carboplatin AUC was also measured based on a single-sample method and the results were compared with the calculated AUC. The end points of the trial were complete pathologic remission (CPR) and crude survival. RESULTS: Approximately 50% of patients in both arms underwent second-look surgery. The frequency of CPR was 32% and 30%, respectively. The survival curves showed no significant difference (P = .84). The dose-intensity of cyclophosphamide was almost identical in the two arms, whereas that of carboplatin was different. In the AUC8 arm, the dose-intensity was 1.86 times that of the AUC4 arm. The results also demonstrated good agreement between the calculated and the measured AUC in most patients. Bone marrow toxicity was significantly higher in the AUC8 arm. CONCLUSION: A doubling of the carboplatin dose-intensity did not result in any significant improvement of pathologic remission or survival. Calvert's formula can be used to give a fairly accurate estimate of the carboplatin AUC. Bone marrow toxicity increased with higher dose-intensity, and a further increase of dose is only feasible with growth-factor or stem-cell support.

Endometrial carcinomas--flow cytometric DNA content and S-phase values.

The purpose of the investigation was to determine the DNA content and S-phase value in a large material of fresh tumour tissue from endometrial carcinomas and to correlate these parameters to tumour type, grade of differentiation, depth of myometrial invasion and stage. The prospective study consisted of 290 unselected cases of endometrial carcinomas, FIGO stage I-IV where flow cytometry was performed on fresh tumour tissue blocks from hysterectomy specimens. 223 cases had more than 10% tumour tissue in tissue blocks taken adjacent to the blocks for flow cytometry. Non-diploidy was defined as 0.9 > or = DNA index > 1.10 and high S-phase value was defined as > 15%. Non-diploidy was found in 46% of the endometrioid adenocarcinoma and in 85% of the non-endometrioid carcinomas (clear cell adenocarcinoma, serous adenocarcinoma and malignant mixed mesodermal tumour) (p < 0.001). S-phase value was > 15% in 39% of the endometrioid adenocarcinoma and in 100% of the non-endometrioid carcinomas (p < 0.0001). In endometrioid adenocarcinoma there was a statistical significant relation between non-diploidy and grade of histological differentiation (p < 0.006), as well as with depth of myometrial invasion (p < 0.05). There was no relation between non-diploidy and the presence of squamous differentiation, whether benign or malignant or to FIGO stage. High S-phase values (> 15%) was related to the grade of differentiation (p < 0.002). No relation was demonstrated between S-phase > 15% and squamous differentiation, depth of myometrial invasion or FIGO stage. In conclusion, 50% of all the endometrial carcinomas were non-diploid and 43% had S-phase value > 15%. Ploidy correlated with histologic tumour types, grade of differentiation and depth on myometrial invasion while S-phase values only correlated with histologic tumour types and grade of differentiation.

Interobserver agreement for tumour type, grade of differentiation and stage in endometrial carcinomas.

The histopathologic evaluation plays a major role in subdividing endometrial carcinomas into treatment groups. We have evaluated the interobserver agreement regarding tumour type, grade of differentiation, stage and stage I low and high risk cases. A total of 177 cases of endometrial carcinoma in which a hysterectomy and a bilateral salpingo-oophorectomy were performed, were reviewed by three examiners. A variety of features including tumour type, architectural grade, nuclear grade, FIGO grade, and spread/metastases were recorded, and the FIGO stage was determined. Using two different definitions low and high risk groups in stage I tumours were separated. A kappa value was calculated for each of the various parameters. The current study showed a good strength of agreement for tumour type, myometrial invasion, spread/metastases, and FIGO stage (kappa 0.62-1.00). For two of the examiners good agreement was found as to architectural grade (kappa 0.71) while the kappa value for nuclear grade was lower (0.56). As nuclear grading is included in the revised FIGO recommendation a precise definition of nuclear atypia is needed. In stage I tumours very good agreement was demonstrated as to the defined low and high risk group (Kappa 0.64-0.86).

Long-term survival and prognostic factors in advanced epithelial ovarian cancer with special emphasis upon the effects of protocol inclusion.

The Danish Ovarian Cancer Study Group registered 722 patients in stages III and IV during the period 1981-1986. The material included 85% of all ovarian cancer patients in the catchment area of the group and patients allocated to protocol as well as patients treated outside protocols. Five and 10-year survival were: stage III 17%, and 8%, respectively; and stage IV 4% and 2%. Patients allocated to protocol had a significantly better survival than patients not included in protocols even when only patients younger than 70 years were compared. All non-protocol patients had a poorer prognosis irrespective of the reason for exclusion. Five-year survival for stage III protocol patients was 25% vs. 9%, for non-protocol patients younger than 70 years. The 10-year survival was 11% and 4% for stage III protocol and non-protocol patients, respectively. A multivariate analysis showed that residual tumor, age, stage, and performance status had prognostic value. In non protocol patients histologic grade had an additional marginal prognostic impact. In conclusion the study showed that the statement that long-term survival in advanced ovarian cancer has been increased could not be proven by comparison of survival from randomized studies performed in the early eighties with survival of stage III and IV patients before the introduction of cisplatinum chemotherapy. It is necessary to consider survival of all patients, protocol and non-protocol in a geographically well-defined region for evaluation of survival improvement.

Prognostic factors and adjuvant treatment in early epithelial ovarian cancer.

Four hundred and ten patients with epithelial ovarian cancer FIGO stages I and II were registered by a Danish multicenter study group (The Danish Ovarian Cancer Group - DACOVA). Two-thirds were stage I, the most frequent substage was Iai which was the classification in 27%. Five-year survival for stage I was 72%, and 38% for stage II. Multivariate analysis showed that age, stage, residual tumor, histologic grade and adjuvant treatment had prognostic value. For stage, three significantly different groups could be identified: (1) stage Iai, (2) stage Iaii-Ic, and (3) stage II. Histologic grade showed a significant survival difference between all grades. Adjuvant treatment had a moderate but significant impact on survival. Patients in stage Iai had a good survival with surgery alone and will probably not benefit from adjuvant therapy. Adjuvant treatment improved survival for the remaining patients in stages I and II without residual tumor. A difference between treatment modalities was not observed. However, the data need to be confirmed by a randomized trial. Patients in stage II with residual tumor should be treated as stage III.

A prospective randomized comparison of 6 and 12 cycles of cyclophosphamide, adriamycin, and cisplatin in advanced epithelial ovarian cancer: a Danish Ovarian Study Group trial (DACOVA).

Two hundred-two patients with FIGO stages III and IV epithelial ovarian cancer were randomized to 6 or 12 cycles of cyclophosphamide, Adriamycin, and cisplatin (CAP). Patients in complete clinical response underwent a second-look laparotomy, 1 month after cessation of chemotherapy. Patients randomized to 6 cycles and found to be in partial remission at second-look were to receive a further 6 cycles of CAP. Rate of complete pathological response was 23% for 6 cycles of CAP and 25% for 12 cycles; the median survival was 23 months for 6 cycles and 27 months for 12 cycles, and 3-year survival was 29% for 6 cycles and 35% for 12 cycles. None of these differences were statistically significant. Fifty-four patients randomized to 6 cycles were found to be in partial surgical remission at second-look laparotomy, and 24 of these patients agreed to a further 6 cycles and a third-look laparotomy. Six of these 24 patients had a complete pathological response at third-look, improving the complete response rate to 28% in those originally randomized to 6 cycles. However, 3 of these patients all had macroscopic tumors removed at second-look, and two had microscopic disease at second-look. Among patients achieving complete response mean cumulative doses in the CAP 6 cycle group were approximately 50% of those in the CAP 12 cycle group. However, when all patients were considered, this difference was only approximately 15% owing the continuation of chemotherapy in the partial responders of the 6 cycle group and early stopping for chemotherapy in the CAP 12 cycle group due to toxicity or progression. Patients in complete pathological response also showed similar survivals for 6 and 12 cycles. In conclusion, the study did not show a correlation between mean cumulative doses and complete pathological response and survival.

Epidermoid carcinoma of the pharynx. Therapeutic results in a series of 221 patients.

Two hundred and twenty-one cases of epidermoid carcinoma of the pharynx diagnosed between 1965 and 1984 were analysed. Fifty-seven per cent of the carcinomas were poorly differentiated and 57% of the patients had stage IV disease; 65% had lymph node metastases at the time of diagnosis. Radiotherapy was the primary treatment. Between 1977 and 1979, preirradiation chemotherapy was used and from 1979 the effect of the radiosensitizer misonidazole was investigated in split-course radiotherapy. Loco-regional failure occurred in 60% after primary treatment. No changes in treatment results were observed during four consecutive 5-year periods. The five-year corrected actuarial survival rate in the whole series was 33%. It is concluded that the treatment results are still unsatisfactory, and that chemotherapy, optimized radiotherapy, and radiosensitizers as used in the present series did not seem to improve the results. Alcohol and tobacco restriction is emphasized for prevention.

Randomized study of whole-abdomen irradiation versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer.

From 1 September 1981 to 1 January 1987, 118 patients with FIGO Stage IB, IC, IIA, IIB, and IIC epithelial ovarian cancer were randomized to abdominal irradiation or pelvic irradiation + cyclophosphamide. There was no difference between the regimens with respect to recurrence-free survival (55%) and 4-year overall survival (63%). At routine second-look laparotomy, 16% of patients without clinical detectable tumor showed recurrence. Twenty-five percent of the patients treated with pelvic irradiation + cyclophosphamide had hemorrhagic cystitis, probably caused by radiation damage and cyclophosphamide cystitis. Eight percent had late gastrointestinal symptoms requiring surgery.

The prognostic and therapeutic value of second-look laparotomy in advanced ovarian cancer.

Of 267 patients with ovarian cancer FIGO stages III and IV, 157 underwent second-look laparotomy after combination chemotherapy consisting of cis-platinum and cyclophosphamide with and without doxorubicin. At second-look operation 45% had macroscopic tumour, 15% microscopic tumour, and 40% complete pathological response. Survival 3 years after second look was: complete pathological response 74%; microscopic disease 24%; visible tumour less than 1 cm 28%; visible tumour greater than 1 cm 17%; negative cytology 59%; and positive cytology 18%. Of the patients with macroscopic tumour, 29% had all visible tumour removed at second look. Three-year survival for these patients was about 45%.