Multi-aspect candidates for repositioning: data fusion methods using heterogeneous information sources.

Drug repositioning, an innovative therapeutic application of an old drug, has received much attention as a particularly costeffective strategy in drug R&D Recent work has indicated that repositioning can be promoted by utilizing a wide range of information sources, including medicinal chemical, target, mechanism, main and side-effect-related information, and also bibliometric and taxonomical fingerprints, signatures and knowledge bases. This article describes the adaptation of a conceptually novel, more efficient approach for the identification of new possible therapeutic applications of approved drugs and drug candidates, based on a kernel-based data fusion method. This strategy includes (1) the potentially multiple representation of information sources, (2) the automated weighting and statistically optimal combination of information sources, and (3) the automated weighting of parts of the query compounds. The performance was systematically evaluated by using Anatomical Therapeutic Chemical Classification System classes in a cross-validation framework. The results confirmed that kernel-based data fusion can integrate heterogeneous information sources significantly better than standard rank-based fusion can, and this method provides a unique solution for repositioning; it can also be utilized for de novo drug discovery. The advantages of kernel-based data fusion are illustrated with examples and open problems that are particularly relevant for pharmaceutical applications.

Herbivory and abiotic factors affect population dynamics of Arabidopsis thaliana in a sand dune area.

Population dynamics of the annual plant Arabidopsis thaliana (L.) Heynh. were studied in a natural habitat of this species on the coastal dunes of the Netherlands. The main objective was to elucidate factors controlling population dynamics and the relative importance of factors affecting final population density. Permanent plots were established and plants were mapped to obtain data on survival and reproductive performance of each individual, with special attention to herbivore damage. In experimental plots we studied how watering, addition of nutrients, artificial disturbance, and natural herbivores affected survival and growth. Mortality was low during autumn and early winter and high at the time of stem elongation, between February and April. A key factor analysis showed a high correlation between mortality from February to April and total mortality. The specialist weevils Ceutorhyncus atomus and C. contractus (Curculionidae) were identified as the major insect herbivores on A. thaliana, reducing seed production by more than 40 %. These herbivores acted in a plant size-dependent manner, attacking a greater fraction of the fruits on large plants. While mortality rates were not affected by density, fecundity decreased with density, although the effect was small. Adding water reduced mortality in rosette and flowering plant stages. Soil disturbance did not increase seed germination, but did have a significant positive effect on survival of rosette and flowering plants. Seed production of A. thaliana populations varied greatly between years, leading to population fluctuations, with a small role for density-dependent fecundity and plant size-dependent herbivory.

Transvaginal extraction of the laparoscopically removed spleen.

Laparoscopic removal of normal and moderately enlarged spleens has become the gold standard operation in recent years because its short operative time, technical safety, and quick patient recovery time. The best method for extraction of the removed spleen, however, has not yet been determined. The authors present a new method for the extraction of the laparoscopically removed spleen. Using a transvaginal approach, the organ is removed through an incision on the posterior vaginal wall and exteriorized in a laparobag. The procedure is similar to a routine vaginal hysterectomy, but is technically much simpler to perform.

Correlation of prenatal clinical findings with those observed in fetal autopsies: pathological approach.

Our objective was to present a comprehensive description of the clinicopathological findings of 173 abortions, including 121 therapeutic and 52 spontaneous ones in the period between 1992 and 1998. In all of these fetuses pathological examination was carried out. It was complemented when indicated by immunohistochemistry, in situ hybridization, flow cytometry, and X-ray examination. In the 121 therapeutic abortions the distribution of malformations was: 45 central nervous system anomalies (37%), 12 genitourinary anomalies (10%), 25 gastrointestinal anomalies (21%), two respiratory system anomalies (1.65%), eight cardiac anomalies (6.6%) and 28 other anomalies (17.2%) as revealed by autopsy. From the clinically selected 52 spontaneous abortions, major malformations were seen in 15/52 cases. With the comparison of the pathological and clinical findings in 121 therapeutic abortions, the percentage of cases with correct clinical designation and no missed anomalies amounted for 49%. However in 51% additional or different lethal, severe, or major malformations were revealed or excluded by fetopathological examinations. In 4% the clinical observation and diagnosis were modified, but without implications for the therapeutic termination of pregnancy. The clinical indication could not be supported in another 3% of the cases.

[Parvovirus B19 infection in hydrops fetalis]. / Parvovírus B19-infekció foetalis hydropsban.

In a retrospective study from 210 foetal autopsies carried out in a period between 1992 and 1999 fifteen hydropic foetuses were found. The cause of the hydrops was shown to be Rh incompatibility in one case only. The cause of hydrops was not discernible in one case. In the others pathological examination clarified the cause and pathomechanism of non-immune hydrops. One isolated cystic hygroma, one monochorionic twin pregnancy with twin to twin transfusion, one case of sacrococcygeal teratoma and 4 cases of congenital heart diseases were reported. Postmortem interphase cytogenetic examination showed X0 monosomy in 2 cases. In further 4 foetuses pathognomic viral inclusions in the proerythroblasts raised the probability of parvovirus B19 infection what was confirmed by immunohistochemistry and electronmicroscopic examination. The occurrence of the parvovirus B19 associated cases of foetal hydrops was shown to be higher (4/15) in this series than in the literature. The accumulation of cases in 1998 is suggestive of an outbreak. The prenatal diagnostic implications and the attempts on further management are also discussed.

Twin pregnancy following in vitro fertilisation coinciding with laryngeal cancer.

The authors report the case of a 33-year-old female patient who was admitted to their Department with supraglottic laryngeal cancer detected in the 1st trimester of her twin pregnancy following in vitro fertilisation after a 10-year nulliparous period of her married life. Since a horizontal supraglottic laryngectomy performed during pregnancy the patient has been free of recurrences, and the twins delivered 3 years ago are in good health. According to the authors, of all available therapeutic possibilities (surgery, cytostatic drugs, telecobalt irradiation) in pregnancy coinciding with laryngeal cancer, optimal therapeutic effects can be achieved by surgery.

Closure or non-closure of visceral peritoneums after abdominal hysterectomies and Wertheim-Meigs radical abdominal hysterectomies.

The effect of visceral peritoneal closure after conventional abdominal hysterectomies and Wertheim-Meigs radical operations was studied clinically. No considerable differences were found in the postoperative staying period; however, the incidence of complications were less in the peritoneal non-closure group (n = 91) than in the control, peritonealized group (n = 149). Significantly lower was the number of postoperative irregular pyelogram in cases without peritoneal closure (n = 25) of radical abdominal operations than in the control group (n = 49) with peritoneal suturing. We therefore suggest that the lack of suturing of visceral peritoneums has some advantages after abdominal hysterectomies and especially has benefits for Wertheim-Meigs operations.

[Dopamine, noradrenaline and serotonin levels in amniotic fluid during the second trimester in normal and pathologic pregnancy]. / A magzatvíz dopamin, noradrenalin és szerotonin értékei a terhesség második trimeszterében, normális és kóros kimenetelü terhességekben.

Authors measured the dopamine (DA), noradrenaline (NA) and serotonin (5-HT) contents of amniotic fluid between 19 and 21 weeks with fluorimetric method. The amniotic fluid samples were obtained by transabdominal amniocenteses performed due to elevated maternal serum-alphafetoprotein levels and suspect ultrasound findings. They considered as normal values the average of 30 amniotic fluid samples obtained from pregnant women who gave birth to healthy babies at term. The mean values (mean+SE) of normal cases were 136.6 + 20.2 nmol/l for DA, 29.5 + 9.4 nmol/l for NA and 72.6 + 4.9 nmol/l for 5-HT. Against these values, in cases of open spina bifida the level of NA showed no significant difference, the DA level was higher (p < 0.05) and the 5-HT level was also higher (p < 0.001). The DA level was found higher (p < 0.05) in cases of intrauterine retardation as well, however there was no difference in the NA and 5-HT levels in these cases. In cases of preterm deliveries, none of the above parameters showed differences. Authors suggest that in cases of spina bifida the measurement of 5-HT in the amniotic fluid can be a complementary diagnostic method. They also state that no prognosis about the outcome of pregnancies can be expected from such examinations.

[Exclusion of Sandhoff disease (Tay-Sachs 0 variant) by chorion biopsy]. / Sandhoff-betegség (Tay-Sachs 0 varians) kizárása chorionbiopszia segítségével.

Transcervical chorionic villus sampling with ultrasound guidance at the 11-th week of pregnancy was made at a woman with the history of one lethal case of Sandhoff disease. The total hexosaminidase and the hexosaminidase A were determined. At the 16-th week amniocentesis was performed and the characteristic enzymes were determined from the amniotic cell culture. The results of the examinations made possible to advise the patient to carry out the pregnancy. The examinations after delivery confirmed the newborn to be a carrier.

[Treatment of cervical cancer using the Wertheim-Latzko radical operation at the Gynecology Clinic of Pécs]. / Méhnyakrákok gyógyítása Wertheim--Latzko radikális mütéttel a Pécsi Nöi Klinikán.

The authors performed 119 Wertheim--Latzko operations from July 1, 1975 to December 31, 1988. 108 patients are still alive. The 5 years survival rate of patients operated on before 1984 was 89.8%. Radical hysterectomy involving careful removal of regional lymphnodes was carried out after lymphography and preoperative irradiation. Postoperative irradiation was made on radiologist's indication. Significance of combined surgical and radiotherapy is emphasised in the management of cervical cancer in stages IB and IIA. Surgery is especially important in adenocarcinomas that are less sensitive to irradiation, in cases of large and necrotic tumors with the barrel formation of endocervical cavity and in cases not showing appropriate regression after radiotherapy. Surgical tumor removal appears to be of much value in young patients, in cases of anaplastic tumors in suspicious lymphographic findings, and in those patients, whose recovery may be expected only from operation and supplementary radiotherapy. Very important condition for obtaining good recovery results and low rate of surgical complications are the team of experienced surgeons and organized regional centres for radical hysterectomies.

Serum levels of placenta-specific tissue protein 12 (PP12) in pregnancies complicated by pre-eclampsia, diabetes or twins.

PP12 is one of the recently discovered soluble tissue antigens of the placenta. During normal pregnancy maternal serum PP12 levels rise during the first 18 weeks reaching a mean peak value of 139.9 +/- 40.26 micrograms/l; after that there is a fall to a mean value of 111.9 +/- 42.39 micrograms/l between 28 and 40 weeks. Significantly higher mean serum PP12 levels were found in the third trimester in two high risk pregnancy groups (281.09 +/- 117.08 micrograms/l in pre-eclamptic toxaemia and 203.71 +/- 73.77 micrograms/l in diabetes) while serum PP12 levels remained normal (114.94 +/- 58.06 micrograms/l) in twin pregnancy. The increase of serum PP12 concentration in toxaemia and in diabetes may be of considerable diagnostic significance.

Levels of placenta-specific tissue protein 12 (PP12) in serum during normal pregnancy and in patients with trophoblastic tumour.

A sensitive radioimmunoassay method has been developed to measure soluble placental protein 12. Using this method trace amounts of PP12 have also been detected in the sera of healthy non-pregnant subjects (24.0 +/- 6.15 micrograms/l). During normal pregnancy serum PP12 levels rose rapidly reaching a peak value of 139.90 +/- 40.26 micrograms/l at 18 weeks. Serial determinations of PP12 have been made in 31 patients with trophoblastic tumours (16 hydatidiform moles, 10 invasive moles and five choriocarcinomas). It has been found that in patients with hydatidiform and invasive moles its initial values are extremely high (342.9 +/- 257.9 micrograms/l and 279.3 +/- 103.1 micrograms/l, respectively), much exceeding the non-pregnant and normal pregnant values. After evacuation of hydatidiform moles serum-PP12 rapidly fell to the upper limit of normal at 21-28 days, and to normal values at 8-12 weeks after operation. In patients with invasive mole requiring chemotherapy the rate of fall of PP12 level was slower. In patients with choriocarcinoma serum-PP12 levels were moderately raised (59-132 micrograms/l) and followed the clinical course of the disease. Serum-PP12 levels would seem to be of less value in monitoring patients with trophoblastic tumours than other tumour-markers (hCG, and SP1).

The prognosis of the possible foetal and placental complications during delivery by measuring maternal serum levels of pregnancy-specific beta-1-glycoprotein (SP1).

The correlation between pathological maternal SP1 serum levels and possible foetal complications during delivery was studied. In 1954, SP1 measurements were made in 823 pregnant women between the 32nd and 40th gestational weeks. On the basis of SP1 serum concentrations groups of patients were formed. The results clearly show that pathological SP1 serum concentrations are frequently associated with intrauterine growth retardation of the foetus, imminent intrauterine asphyxia, and cesarean section indicated by foetal distress. The SP1 placental function-test is recommended as a simple, inexpensive screening method for the detection of placental insufficiency.