Angiostatin overexpression in Morris hepatoma results in decreased tumor growth but increased perfusion and vascularization.

Growth of malignant tumors is dependent on sufficient blood supply. Thus, inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Human angiostatin (hANG) is one of the most potent inhibitors of endothelial cell proliferation, angiogenesis, and tumor growth in vivo. However, its mechanisms operating in vivo are not well understood. METHODS: To obtain more information about functional changes in the angiogenic process, we established Morris hepatoma (MH3924A) cell lines expressing hANG (hANG-MH3924A). The effects of hANG expression on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) were measured in coculture experiments in vitro. To evaluate changes in tumor perfusion and blood volume, H2 15O and 68Ga-DOTA-albumin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid) were used for PET studies in vivo. Additionally, immunohistologic quantification of vascularization, apoptosis, and proliferation as well as gene array analyses were performed. RESULTS: Our in vitro experiments demonstrate reduced proliferation and increased apoptosis in HUVECs when being cocultured with hANG-MH3924A. In support, tumor growth of hANG-MH3924A is diminished by 95% in vivo. However, tumor perfusion and blood volume are increased in hANG-MH3924A corresponding to an increased microvessel density. Furthermore, hANG-transfected tumors show changes in expression of genes related to apoptosis, stress, signal transduction, and metabolism. CONCLUSION: hANG expression leads to inhibition of tumor growth, increased apoptosis, and changes in the expression of multiple genes involved in stress reactions, signal transduction, and apoptosis, which indicates a multifactorial reaction of tumors. An enhanced microvessel density is seen as part of these reactions and is associated with increased perfusion as measured by PET.     

Comparison of fecal microflora in children with atopic eczema/dermatitis syndrome according to IgE sensitization to food

Atopic eczema/dermatitis syndrome (AEDS) commonly often arises during early infancy. In several intervention studies a beneficial influence on AEDS course of certain intestinal bacteria, administered as 'probiotics', has been described. To evaluate the possible role of the natural intestinal microflora in children with allergic eczema/dermatitis syndrome regarding immediate type hypersensitivity to food allergens, children with food allergy (AAEDS, n = 68) have been compared with children without detectable food allergy (NAEDS, n = 25). All children (n = 93) in preschool age, mean age of 2.6 (+/-1.8) years, diagnosed with AEDS who were treated as inpatients in 2003 in a dermatological hospital were included. The correlation between fecal microflora, parasites and specific immunoglobulin E (IgE) antibodies against common food allergens was analyzed. A similar composition of intestinal microflora in children with AAEDS and NAAEDS was found. The food allergens that were most frequently detected were egg white, cow milk, casein, peanut and hazelnut. Furthermore, a significant association between IgE sensitization against important food allergens and components of the fecal microflora could not be demonstrated. With aging changes occur in the intestinal microbiota [Proteus/Klebsiella and age (rho = -0.607) and Enterococcus and age (rho = -0.428)]. In two subjects of the AAEDS group Blastocystis hominis was found. The composition of natural intestinal microflora in children with AAEDS and NAAEDS was similar. Hence, there is no evidence of a role of the intestinal microflora with regard to the development of infant (food) allergy in children with AEDS. The possible consequences for allergic diseases later in life require further investigation.     

HEAD CIRCUMFERENCE AND INTELLECTUAL PERFORMANCE OF PATIENTS WITH DUCHENNE MUSCULAR DYSTROPHY

The head circumferences of 64 patients with Duchenne muscular dystrophy were measured and found to be greater than those of a normal population. The patients had relative, and in 12 cases, absolute macrocephaly. 47 of the 64 patients underwent intelligence testing and were found to be significantly intellectually impaired, particularly in verbal and language skills. There was no correlation between head circumference or absolute macrocephaly and intellectual performance. The cause of macrocephaly in these patients is unknown and its relevance to the aetiology of intellectual impairment in Duchenne muscular dystrophy is not yet clear.     

Assessment of an interactive computer-based patient prenatal genetic screening and testing education tool.

The Enhancing Patient Prenatal Education study tested the feasibility and educational impact of an interactive program for patient prenatal genetic screening and testing education. Patients at two private practices and one public health clinic participated (N = 207). The program collected knowledge and measures of anxiety before and after use of the tool. Time in various prenatal visit activities was collected prior to and after the introduction of the education tool. Providers completed an assessment of their experiences with patients who had used the program. Results indicate that patient knowledge significantly increased from pre to post (p = .0001) with no increase in anxiety (p = .31). Time in clinic activities, including overall visit time, increased. A majority of providers indicated that the program disrupted clinic flow. This assessment suggests that the program increases patient knowledge and does not increase patient anxiety. However, challenges remain to using this program in a clinic setting.     

Cesarean delivery during second-stage labor: characteristics and diagnostic accuracy.

OBJECTIVE: To characterize dysfunctional labors that lead to cesarean delivery in the second stage and to assess the accuracy of diagnoses of abnormal fetal descent. METHODS: Thirty-one patients delivered by cesarean during the second stage because of abnormal labor or presumed cephalopelvic disproportion were studied and compared to 62 control cesarean cases delivered for the same indications in the first stage. The clinical diagnosis of dysfunctional labor that led to the cesarean was compared to the diagnosis made by retrospective analysis of the labor curves. RESULTS: Cases did not differ from controls delivered in the first stage in maternal age, race, parity, gestational age, weight gain, or the frequency of associated medical complications. The newborns were not significantly different in birth weight,ponderal index, sex, or the incidence of low Apgar scores. Among study patients, 94% had a second stage labor dysfunction determined by graphic labor analysis, predominantly arrest of descent (69%) and failure of descent (28%). In 79% of cases a dysfunctional first stage preceded the abnormal second stage. Among these first stage labor abnormalities, 68% were not recognized during the labor. CONCLUSION: Characteristics of patients delivered by cesarean during the second stage were similar to those delivered before full cervical dilatation. Second stage labor abnormalities were usually preceded by an abnormal first stage. There was considerable inaccuracy in the diagnosis of second stage labor dysfunction.     

Sites in the male primate brain at which testosterone acts as an androgen

Quantitative autoradiographic analysis was used to identify regions in the brain of the male primate where androgen binding sites may be involved in the actions of testosterone. Three days after castration, adult male rhesus monkeys received a subcutaneous injection of either dihydrotestosterone propionate (DHTP, 20 mg, n = 6), testosterone propionate (TP, 100 mg, n = 2), or oil vehicle (control males, n = 4). Three hours later, 5 mCi [3H]testosterone was administered as an i.v. bolus. At 60 min, brains were rapidly removed and the left halves were used for autoradiography. In control males, highest percentages of labeled neurons (20-84% using a rigorous Poisson criterion) were observed in the ventromedial, arcuate and premammillary nuclei (n.) of the hypothalamus, medial preoptic n., bed n. of stria terminalis, intercalated mammillary n., lateral septal n. and the medial, cortical and accessory basal n. of the amygdala. Pretreatment with DHTP eliminated labeling in androgen target tissues of the genital tract, and reduced the percentages of labeled neurons to 4-22% of control values in the arcuate, lateral septal, premammillary and intercalated mammillary n., indicating that in these regions testosterone acted predominantly at androgen binding sites. However, in the medial preoptic n., the ventromedial hypothalamic n. and the accessory basal amygdaloid n., DHTP pretreatment resulted in much less blocking which, together with other data, suggested that in these sites, testosterone's actions involved aromatization and interaction with estrogen-binding sites.     

Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg

To cover intermediate sensitive Candida glabrata in ICU patients,fluconazole plasma peak levels at least in the range of 16–32µg/ml appear necessary for treatment. Previous studiesdid not reach these fluconazole levels under continuous veno-venoushaemofiltration (CVVHF) with dosages of 200–600 mg fluconzoledaily. In the present study, nine patients simultaneously requiringCVVHF for treatment of acute oligoanuric renal failure and antimycotictherapy of Candida septicemia received fluconazole 800 mg/day.Fluconazole plasma levels were determined to evaluate whetherthis dosage is adequate to reach the advised fluconazole levels.Patients were dialysed on two consecutive days with an ultrafiltrationrate (UF) of 1000 ml/h or 2000 ml/h, respectively, in a randomizedorder. The predilution was 800 ml/h and 1800 ml/h, respectively.The treatment was tolerated without adverse effects. All patientsreached plasma fluconazole concentrations between 16 and 32µg/ml, remaining in this range for a minimum of 1 up to24 h with a mean of 9.6 h and a UF rate of 2000 ml/h, and 15.7h with a UF rate of 1000 ml/h. So far, there are no in vivodata on the fluconazole plasma concentrations required for effectivetreatment. However, our data demonstrate, that at least thefluconazole concentrations desirable on the basis of in vitrosusceptibility testing can be reached in critically ill patientson CVVHF in an ICU setting. However, in these patients, 800mg fluconazole/day are necessary to achieve fungicidal drugconcentrations.