Learning cyclic signaling pathway structures while minimizing data requirements.

Bayesian network structure learning is a useful tool for elucidation of regulatory structures of biomolecular pathways. The approach however is limited by its acyclicity constraint, a problematic one in the cycle-containing biological domain. Here, we introduce a novel method for modeling cyclic pathways in biology, by employing our newly introduced Generalized Bayesian Networks (GBNs). Our novel algorithm enables cyclic structure learning while employing biologically relevant data, as it extends our cycle-learning algorithm to permit learning with singly perturbed samples. We present theoretical arguments as well as structure learning results from realistic, simulated data of a biological system. We also present results from a real world dataset, involving signaling pathways in T-cells.

On the origin of the invasive olives (Olea europaea L., Oleaceae).

The olive tree (Olea europaea) has successfully invaded several regions in Australia and Pacific islands. Two olive subspecies (subspp. europaea and cuspidata) were first introduced in these areas during the nineteenth century. In the present study, we determine the origin of invasive olives and investigate the importance of historical effects on the genetic diversity of populations. Four invasive populations from Australia and Hawaii were characterized using eight nuclear DNA microsatellites, plastid DNA markers as well as ITS-1 sequences. Based on these data, their genetic similarity with native populations was investigated, and it was determined that East Australian and Hawaiian populations (subsp. cuspidata) have originated from southern Africa while South Australian populations (subsp. europaea) have mostly derived from western or central Mediterranean cultivars. Invasive populations of subsp. cuspidata showed significant loss of genetic diversity in comparison to a putative source population, and a recent bottleneck was evidenced in Hawaii. Conversely, invasive populations of subsp. europaea did not display significant loss of genetic diversity in comparison to a native Mediterranean population. Different histories of invasion were inferred for these two taxa with multiple cultivars introduced restoring gene diversity for europaea and a single successful founder event and sequential introductions to East Australia and then Hawaii for cuspidata. Furthermore, one hybrid (cuspidata x europaea) was identified in East Australia. The importance of hybridizations in the future evolution of the olive invasiveness remains to be investigated.

Bubble statistics and dynamics in double-stranded DNA.

The dynamical properties of double-stranded DNA are studied in the framework of the Peyrard-Bishop-Dauxois model using Langevin dynamics. Our simulations are analyzed in terms of two distribution functions describing localized separations ("bubbles") of the double strand. The result that the bubble distributions are more sharply peaked at the active sites than thermodynamically obtained distributions is ascribed to the fact that the bubble lifetimes affect the distributions. Certain base-pair sequences are found to promote long-lived bubbles, and we argue that this is a result of length scale competition between the nonlinearity and disorder present in the system.

Stavudine versus zidovudine and the development of lipodystrophy.

The pathogenesis of some components of the lipodystrophy (LD) syndrome might be linked to the use of nucleosides. Earlier reports did not compare treatment regimens according to the nucleoside backbone. We studied a cohort of individuals who did not switch between stavudine and zidovudine. LD was defined to be present if one of three criteria was met: self-report by the patient, observation by an investigator who had known the patient since commencement of highly active antiretroviral therapy (HAART), or examination by a physician masked to therapy. The mean duration of therapy was 101 weeks (range: 26-234 weeks). Overall prevalence of LD was 48.7%. Lipoatrophy and lipohypertrophy occurred in 33.9% and 28.7% of patients, respectively. Logistic regression showed four parameters to be significantly associated with lipoatrophy: HAART longer than 2 years (p =.002, odds ratio [OR] = 4.4, 95% confidence interval [CI]: 1.608-11.965), baseline viral load >100,000 copies/ml (p =.004, OR = 4.3, CI: 1.726-11.197), age >40 years (p =.016, OR = 3.2, CI: 1.247-8.373), and white ethnicity (p =.041, OR = 5.4, CI: 1.070-28.184). Cholesterol levels of >200 mg/dl at baseline were associated with a risk reduction (p =.047, OR = 0.36, CI: 0.130-0.987). Use of lipohypertrophy as a dependent variable resulted in a significant association with HAART duration (p = 0.028, OR = 2.7, CI: 1.2-6.5) and protease inhibitor use (p =.014, OR = 3.8, CI: 1.3-11.2). LD prevalence is similar with both backbones using stavudine or zidovudine. This is the first time that baseline cholesterol was shown to be significantly associated with lipoatrophy.

Gender-specific health behaviors of German university students predict the interest in campus health promotion.

This cross-sectional study aimed to provide an assessment of the needs for health promotion in university freshmen, based on lifestyle variables and the interest in health-promoting activities. A questionnaire survey was performed using a sample of 288 male and 362 female university freshmen from 19 to 33 years of age. Male students were significantly more likely to engage in drug-taking behaviors, referring to alcohol and cannabis use, and had a higher body mass index. No gender difference was noted in the numbers of regular smokers. Preventive behaviors with respect to healthy nutrition and dental hygiene were reported more often in females, whereas the duration of physical activity per week and the use of condoms with a new sexual partner showed no gender difference. There was a strong demand for group health-oriented programs (79.5% of respondents). Substantial proportions of students had a high interest in individual counseling aiming at stress management (24.5%), healthy nutrition (19.3%) and prevention of sexually transmitted diseases (18.2%). Women expressed a greater interest in most programs than men. Multivariate regression analyses showed that a disposition for alcohol abuse was the strongest predictor of interest in health counseling in male students (p < 0.001), while psychosocial stress was the most important predictor in female students (p < 0.001). From the prevalence of health risks and the students' interest in health promotion programs it was concluded that there is a strong need for health promotion in the university setting in Germany. Results suggested that individuals at risk would probably benefit most from an individual counseling program.

New approaches for genotyping of Helicobacter pylori based on amplification of polymorphisms in intergenic DNA regions and at the insertion site of the cag pathogenicity island.

The population of the gastric pathogen Helicobacter pylori shows a high degree of genetic diversity. It is well established that heterogeneity at the isolate level is caused by nucleotide transitions within genes, differences in the gene order, and by genetic instability of single genes as well as of a large virulence-associated genomic DNA region, the cag pathogenicity island (PAI). Analysis of intergenic regions with specific PCR-assays developed in this study, revealed that DNA polymorphisms in the noncoding DNA localized in front of the genes ribA and vacA and at the insertion site of the cag PAI contribute to the genetic diversity of H. pylori and are useful for differentiation of individual isolates. Thirteen individual genotypes were identified by PCR analysis of these polymorphic loci in 487, 241, and 182 clinical H. pylori isolates. Sequence analysis revealed that genetic variability in front of genes ribA and vacA, and in the intergenic region at the PAI insertion site is caused by insertion and deletions of so-far-unknown DNA sequences as well as by parts of the H. pylori IS elements IS605 and IS606, respectively. The new genotypes identified could be used to differentiate antrum and corpus isolates from the same patients. Their combination with vacA allele subtypes and with the cagA status allowed to differentiate 140 isolates in 51 subtypes. In 36 cases the corresponding genotype patterns were isolate specific. In summary, the results confirm that DNA polymorphisms in intergenic regions contribute to the genetic diversity of H. pylori. Although individual H. pylori genotypes were not associated with peptic ulcer disease, the PCR-based approaches for their detection developed here should be of use for further investigation of genetic diversity in H. pylori and for epidemiological purposes.

Cutaneous malignant melanoma in women and the role of oral contraceptives.

The role of oral contraceptives (OC) in the aetiology of cutaneous malignant melanoma (CMM) has been controversially discussed over the last two decades. In an extensive literature search we identified 18 case-control studies, published between 1977 and 1996, offering information on this relationship. Using a meta-analytical approach we combined the study-specific risk estimates and derived a summary odds ratio of 0.95 (95% confidence interval: 0.87-1.04). Based on the data of 3796 cases and 9442 controls, we thus found no evidence for an aetiological role of OC use in the development of CMM.

PIP: The possible association between cutaneous malignant melanoma (CMM) and oral contraceptive (OC) use was explored through a review of the 18 case-control studies on this relationship published during 1977-96. These studies encompassed 3796 cases and 9442 controls. Although the odds ratios (ORs) ranged widely, from 0.13 to 1.85, most studies (14 of 18) produced similar ORs within the interval 0.82-1.15. The summary OR for the total sample was 0.95 (95% confidence interval: 0.87-1.04). Thus, the meta-analysis pointed to an absence of any effect of OCs on the risk of CMM. Separate analyses based on design factors such as type of exposure ascertainment (personal, telephone interview, postal interview, or register information) or the origin of control groups (population or hospital) failed to change this trend. Only 2 prospective cohort studies on this association were located. The estimated risk ratios in these studies, 0.92 and 0.85, each accompanied by wide confidence intervals due to small numbers of cases (58 and 32, respectively), provided additional support for the conclusion that OC use has no detectable effect on CMM risk.

Systematic review of case-control studies: oral contraceptives show no effect on melanoma risk.

BACKGROUND: Parallel to the rising incidence of malignant melanoma in fair-skinned populations, intensive efforts are currently devoted to identifying risk factors for melanoma in addition to the well-known cutaneous factors and those variables related to UV-exposure. OBJECTIVE: Systematic review of published results to elucidate the role of oral contraceptives in the development of malignant melanoma. DATA SOURCES: Literature retrieval systems MEDLINE and CANCERLIT as well as reference lists of already collected studies. STUDY SELECTION: All 18 (non-duplicate) case-control studies on the above relationship. DATA EXTRACTION: From the published data, study-specific odds ratios (OR) and accompanying confidence intervals (CI) were recalculated. For a quantitative meta-analytical summarisation two different models have been applied: a "fixed effects" (FE) and a "random effects" (RE) model. DATA SYNTHESIS: Study-specific ORs ranged from 0.13 up to 1.85; however, the majority of studies (14 of 18) yielded similar ORs within the interval [0.82, 1.15]. The summary ORs estimated from FE- and RE-models were both 0.95 (95% CI: [0.87, 1.04] for the FE-model, [0.87, 1.05] for the RE-model). CONCLUSION: The systematic review of case-control studies revealed no evidence for an aetiological role of oral contraceptives in the development of malignant melanoma.

PIP: A systematic review of the research literature was conducted to elucidate the role of oral contraceptives (OCs) in the development of malignant melanoma. The retrieval systems MEDLINE and CANCERLIT identified 18 case-control studies of this relationship and study-specific odds ratios (ORs) were recalculated in the meta-analysis. These ORs ranged from 0.13 to 1.85; however, the majority of studies yielded ORs within the 0.82-1.15 range. The summary ORs estimated from both fixed effects and random effects models were each 0.95; the 95% confidence intervals were 0.87-1.04 and 0.87-1.05, respectively, indicating no association. Separate analyses of the OC-malignant melanoma association by year of study publication, type of case group, source of the control group, and type of exposure ascertainment corroborated this lack of significant effect.

[Fibrosing alveolitis in a 7-year-old girl with autoimmune hemolytic anemia and autoimmune hepatitis]. / Fibrosierende Alveolitis bei einem sieben Jahre alten Mädchen mit autoimmunhämolytischer Anämie und Autoimmunhepatitis.

A Coombs-positive haemolytic anaemia with proof of heat autoagglutinins and autoantibodies against cell nuclei was diagnosed in a girl, now 7 1/2 years of age, in the sixth month of her life as a sequel to jaundice. Shortly afterwards liver biopsy yielded a confirmed diagnosis of giant cell hepatitis. The signs of the disease receded under treatment with decortin and imurek. An attempt to discontinue the medication at 5 1/2 years of age resulted in a histologically confirmed recurrence of autoimmune hepatitis. When the patient was 5 years old, the x-ray revealed a mainly interstitial pneumonia; at 6 years of age, bronchiectases in the region of the left lower lobe were confirmed by bronchography. Resection of the lower lobe was performed after occurrence of atelectasis. Histopathological findings confirmed fibrotic alveolitis associated with giant cells. Based on the overall clinical course and the histological and immunological findings, autoimmune etiology of fibrotic alveolitis must be discussed. Progression of the disease could be avoided during the past 6 months by intensifying the immunosuppressive prednisolone therapy.

Alteration of the lung parenchyma associated with autoimmune hepatitis.

The clinical history, radiological and histomorphological alterations of the lung parenchyma associated with chronic active autoimmune hepatitis are described. A 6-month-old female infant developed chronic active autoimmune hepatitis associated with autoimmune haemolytic anaemia. She was treated with immunosuppressive drugs, including steroids, for more than 6 years and developed symptoms and radiological signs of interstitial pneumonitis 4 years after onset of the autoimmune hepatitis. Associated bronchiectasis was detected 1 year later. No abnormalities of lung defence mechanisms could be demonstrated. Resection of the sixth left segment and of the basal parts of the left lower lobe revealed honeycombing with changes in the lung parenchyma which included chronic interstitial pneumonitis with multinucleate giant cells, seen predominantly in the distal airways, marked diffuse interstitial mononuclear infiltrates and mild diffuse interstitial fibrosis as well as bronchiectasis and organizing pneumonia. Granulomatous lesions, angiitis and necrotic areas were absent. Immunohistochemistry for immunoglobulins was negative for IgA, IgG and IgM and positive for IgD in the multinucleate giant cells. A strong positive reaction to HLA-DR-specific monoclonal antibody was noted, whereas no specific sugar receptors (endogenous lectins) could be detected by use of biotinylated glyconeoproteins.

Vitamin D requirements and vitamin D intoxication in infancy.

Without vitamin D supplementation, the majority of infants seems to be at risk of vitamin D-deficiency rickets. On the other hand, routine vitamin D supplementation of breast-fed infants is not recommended by all authors. In this paper we give an overview of vitamin D metabolism and vitamin D regulation in newborns, which may differ in a certain way from the regulation in adults. Based on this, minimal and optimal requirements for vitamin D in newborns and infants is determined. Furthermore, the paper aims at defining dosages and conditions that are at risk of vitamin D intoxication.

Terfenadine treatment of fall hay fever.

A double-blind, parallel, multicenter study was undertaken in 215 ragweed skin test positive-patients with fall hay fever. The patients were randomized and treated for seven days with either 60 mg terfenadine twice daily, morning and evening, and a placebo at noon, or with 4 mg chlorpheniramine or placebo three times daily. The severity of nasopharyngeal itching, sneezing, rhinorrhea, nasal congestion, and itchy, watery, red eyes was ranked daily by patients and evaluated before and after treatment by the physician investigators. The patients reported a significant reduction in symptoms within one day. The physician investigators detected moderate to complete relief of symptoms in a greater proportion of the patients treated with terfenadine (70%) and chlorpheniramine (73%) than in the placebo-treated patients (48%). The incidence of sedation with terfenadine treatment (2.5%) was not different from that with placebo (2.4%) and both were lower than with chlorpheniramine (7.6%). We conclude that terfenadine is as effective as chlorpheniramine for the treatment of fall hay fever and that, unlike chlorpheniramine, the incidence of sedation with terfenadine was not different from placebo.

[Fetal and neonatal ascites: a report of 15 cases and a review of the literature]. / Fetaler und neonataler Aszites: Bericht über 15 Fälle und Literaturübersicht.

Fifteen patients with non-immune fetal or neonatal ascites and absence of generalized edema are described. Nine patients were diagnosed prenatally. Nine patients were preterm. Artificial ventilation was necessary in twelve infants immediately after birth. In five cases, including two cases of transitory ascites, the etiology could not be established. In accordance with previous reports, we found the following underlying disorders in our patients: urinary tract obstruction, polycystic disease of the kidneys, chylous ascites, sepsis, intrahepatic atresia of the biliary ducts, hepatic and renal failure following severe asphyxia. 8 out of 15 patients died. A survey of the literature shows a variety of underlying disorders. Therefore, several diagnostic tests are necessary, in order to identify the etiology. Causative treatment is possible in some cases of urogenital , gastrointestinal, infectious and chylous ascites. Sophisticated perinatal management is essential for the outcome of patients with fetal or neonatal ascites; nevertheless the mortality rate is still about 50%.

[Early prognosis of intracranial hemorrhage in premature infants]. / Zur Frühprognose der intracraniellen Blutung bei Frühgeborenen.

Between July 1979 and June 1984 an intracerebral haemorrhage developed in 87 premature infants (mean gestational age 29.5 weeks, mean birth weight 1156g). 46 of these died, 41 infants survived. Their psychomotoric development was followed up to a mean age of 19 months. In 63% of the patients the haemorrhage occurred during the first four days of life. Its frequency was highest in premature infants of 27 to 30 weeks of gestation. The survival rate was influenced by the gestational age and by the grade of haemorrhage. Early complications such as ventricular dilatation, hydrocephalus occlusus and porencephaly were seen especially in very immature infants (less than 31 weeks). The frequency of abnormal psychomotoric development in 55% of these infants contrasts with 13.5% in premature infants (less than 1 500 g) without intracerebral haemorrhage.

Multicenter, double-blind, placebo-controlled trial of terfenadine suspension in the treatment of fall-allergic rhinitis in children.

Children, aged 6 to 12 years, with fall-pollenosis symptoms, were evaluated for their response to a new antihistamine, terfenadine, in a multicenter (six centers) 1-week, double-blind, placebo-controlled trial. All had positive skin tests to grass/weed pollens and/or mold spores prevalent in the fall at each center. Patients were administered placebo or terfenadine as suspension on a randomized basis, with children weighing less than 30 kg receiving terfenadine suspension, 30 mg twice daily, and those weighing greater than 30 kg receiving 60 mg, twice daily. Of the 119 children enrolled, 79 received terfenadine and 40 received placebo. All but two (lost to follow-up) were included for the evaluation of drug safety, whereas 16 were excluded from the efficacy evaluation (11 receiving terfenadine and five receiving placebo) because of protocol noncompliance. Overall, varying degrees of control of symptoms were observed in 85% of the patients in the group taking terfenadine as compared to 60% in the group taking placebo. The symptoms of rhinorrhea, nasal congestion, and sneezing demonstrated the best response. There was no difference between the two groups in adverse events or side effects. Before and after treatment complete blood count, biochemical profile, and urinalysis revealed that there was no change from beginning to end and no difference between the groups. We conclude that terfenadine suspension is a safe, nonsedating antihistamine with an incidence of side effects no different from that of placebo. It is more effective than placebo in controlling symptoms of fall pollenosis in children.

[Non-immunologic hydrops fetalis--report of 14 cases and literature review]. / Nicht-immunologischer Hydrops fetalis--Bericht über 14 Fälle und Literaturübersicht.

With the advent of prenatal diagnosis and the feasibility of intrauterine treatment, non-immune hydrops fetalis (NHIF) is gaining increasing importance. 14 patients are reported 10 of whom having been diagnosed prenatally. 13 were born prematurely severe asphyxia being a frequent occurrence. 7 out of 14 infants survived. In 5 cases no definite etiology could be established. In 7 patients NHIF was attributable to cardiovascular diseases, predominantly associated with brady- or tachycardia. A survey of the literature reveals that etiology remains unidentified in about 40%. For the rest fetal, maternal or placental diseases are the primary causes. The abundance of underlying diseases are operative via three pathophysiological pathways: hemodynamic disturbances, decreased oncotic pressure and increased capillary permeability. By ultrasound examination, NHIF can be detected prenatally permitting intrauterine treatment in selected cases. In combination with improved postnatal management, this might contribute to a better outcome of NIHF which is still associated with a high mortality rate. Meticulous diagnostic work-up facilitates genetic counseling and the pursuit of prenatal diagnosis in subsequent pregnancies.

Intestinal perforation associated with indomethacin treatment in premature infants.

Within 9 months we observed intestinal perforations in three very low birth weight (VLBW) infants undergoing indomethacin treatment for symptomatic patent ductus arteriosus (sPDA). The three patients exhibited striking similarities in their clinical courses and predisposing factors. Although clinical and histological criteria did not differentiate the perforations from necrotising enterocolitis (NEC), a well-known entity in premature infants, these events were remarkable to us since we had observed no other cases of NEC in recent years. From animal experiments and pathophysiological data, a role for indomethacin in gastrointestinal ischaemic damage must be considered. This communication is not meant to discredit indomethacin treatment. However, awareness of potential complications and careful monitoring during treatment is warranted.

Urinary excretion rates of 6-keto-PGF1 alpha in preterm infants recovering from respiratory distress with and without patent ductus arteriosus.

Patency of the ductus arteriosus in preterm infants is mediated by vasodilating prostanoids; however, reliable methods to monitor prostanoid activity or production in preterm infants are lacking. We measured the excretion rates of major and characteristic urinary metabolites of prostacyclin (PGI2), PGE1, and PGE2, 6-keto-PGF1 alpha, and 7 alpha-hydroxy-5,11-diketotetranorprostane-1,16-dioic acid (PGE-M), respectively. Besides these parameters which reflect total body prostanoid turnover and production, the urinary levels of PGE2 and PGF2 alpha, the primary prostaglandins, were measured as an index of renal prostanoid synthesis. There were four study groups. One contained 11 thriving preterm infants; a second, six preterm infants with respiratory distress syndrome (RDS); a third, 30 preterm infants with RDS and patent ductus arteriosus (PDA); and a fourth, nine fullterm infants. All infants with RDS required artificial ventilation. There were no significant differences in PGE-M, PGE2, and PGF2 alpha excretion rates among the various groups; however, a significant increase of the 6-keto-PGF1 alpha excretion rates was observed in the groups of infants with RDS and with and without PDA (P less than 0.01 and P less than 0.02, respectively). Spontaneous (n = 2) or indomethacin-induced (n = 6) closure of PDA was associated with weaning from the respirator and a concomitant drop into the normal and subnormal range of the excretion rates of 6-keto-PGF1 alpha (P less than 0.01) and PGE-M (P less than 0.02).