Mid-childhood outcomes after pre-viable preterm premature rupture of membranes.

OBJECTIVES: Investigate cardiorespiratory outcomes in children surviving previable preterm premature rupture of membranes (PV-PPROM) before 22 weeks' gestational age (GA) with minimum 2 weeks latency. STUDY DESIGN: Single institution, follow-up of retrospectively identified children who were born after PV-PPROM during 2000-2004, and individually matched preterm-born controls. RESULTS: Eleven PV-PPROM and matched control children were included at mean age of 10.5 and 10.7 years. Rupture of membranes occurred at mean GA 182 and 276 weeks and birth at 283 and 286 weeks, respectively. Compared to controls, the PV-PPROM group had significantly poorer lung function, findings on echocardiography indicating mild pulmonary hypertension, and lower peak oxygen consumption. Chart reviews suggested more motor difficulties and a tendency towards more problems with learning and attention. CONCLUSION: The findings highlight a preterm-born sub-group in need of targeted long-term monitoring and possibly interventions regarding future cardiorespiratory and neurodevelopmental function.

Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis.

BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation. METHODS: We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy. RESULTS: EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (>or=40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55). CONCLUSION: Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.

Neonatal bronchopulmonary dysplasia predicts abnormal pulmonary HRCT scans in long-term survivors of extreme preterm birth.

BACKGROUND: There is an increasing understanding that extreme preterm birth carries a risk of long-term pulmonary sequelae. A study was undertaken to investigate if, and in what way, neonatal factors were associated with subsequent abnormalities on pulmonary high-resolution CT (HRCT) scanning and if pulmonary function was related to these abnormalities. METHODS: HRCT scanning and pulmonary function tests were performed less than 2 weeks apart in 74/86 eligible subjects (86%) born at a gestational age of < or =28 weeks or with a birth weight of < or =1000 g within a defined area in Western Norway in 1982-5 (n = 42) or 1991-2 (n = 32). Mean age at examination was 18 and 10 years, respectively. HRCT scans were interpreted by a paediatric radiologist blinded to the clinical data using a structured system allowing scores from 0 to 50. RESULTS: Lung parenchymal abnormalities were found in 64 subjects (86%), the median (interquartile range) score being 3.0 (1.75-5.0) points. Prolonged neonatal requirement for oxygen treatment predicted poor outcome, and an increase of 100 days increased the average HRCT score by 3.8 points (p<0.001). There was also a positive association of the severity of pulmonary function abnormalities with the extent of HRCT abnormalities, exemplified by the relation between forced expiratory volume in 1 s and total HRCT score (beta = -0.090; p<0.001). CONCLUSIONS: In area-based cohorts of long-term survivors of extremely preterm birth, prolonged neonatal requirements for oxygen treatment predicted subsequent structural abnormalities on HRCT scans and in pulmonary function, and these two outcome measures were interrelated.

Pulmonary outcome in adolescents of extreme preterm birth: a regional cohort study.

AIMS: The pulmonary outcome of extreme prematurity remains to be established in adults. We determined respiratory health and lung function status in a population-based, complete cohort of young preterms approaching adulthood. METHODS: Forty-six preterms with gestational age < or = 28 wk or birthweight < or = 1000 g, born between 1982 and 1985, were compared to the temporally nearest term-born subject of equal gender. Spirometry, plethysmography, reversibility test to salbutamol and methacholine bronchial provocation test were performed. Neonatal data were obtained from hospital records and current symptoms from validated questionnaires. RESULTS: When entering the study at a mean age of 17.7 (SD: 1.2) y, a doctor's diagnosis of asthma and use of asthma inhalers were significantly more prevalent among preterms than controls (one asthmatic control compared to nine preterms, all but one using asthma inhalers). Peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) were decreased and the discrepancies relative to controls increased parallel to increased severity of neonatal lung disease. Parameters of increased neonatal oxygen exposure significantly predicted FEV1. Adjusted for height, gender and age, FEV1 was reduced by a mean of 580 ml/s in subjects with a history of bronchopulmonary dysplasia. Fifty-six percent of preterms had a positive methacholine provocation test compared to 26% of controls. CONCLUSION: A substantially decreased FEV1, increased bronchial hyperresponsiveness and a number of established risk factors for steeper age-related decline in lung function were observed in preterms. A potential for early onset chronic obstructive pulmonary disease is present in subsets of this group.

Menometrorrhagia in the perimenopause is associated with increased serum estradiol.

OBJECTIVE: The purpose of this study was to evaluate the possible association between menometrorrhagia and the level of endogenous estrogen in perimenopausal women. METHODS: A prospective controlled study in which 28 perimenopausal women > 40 years presenting with menometrorrhagia were compared with 28 age-matched (+/- 2 years) women with normal cyclical menstrual periods concerning levels of estradiol and follicle-stimulating hormone (FSH). Neither of the two groups had received sexual hormone treatment at least in 2 weeks preceding the hormonal assessment. RESULTS: The serum level estradiol in the patients was significantly higher than in the controls (0.55 nmol/l versus 0.24 nmol/l), whereas FSH was not significantly different between the two groups (21.2 IU/l versus 11.8 IU/l). Twenty of the 28 patients had performed at histologic examination of the endometrium, and 10 of these (50%) had signs of endometrial hyperplasia. No relationship was found between the endometrial histology and the estradiol level. CONCLUSIONS: An association between a high endogenous estradiol level and menometrorrhagia in the perimenopause was demonstrated. This may have implications for the choice of treatment in this group of women. It is proposed that this type of bleeding disturbances should be controlled by progestins only, and not with combined estrogen-progestin treatment. Suppression of the associated hyperestrogenism could be achieved by use of oral contraceptives or GnRH agonists.

Inflammatory aortic aneurysm is associated with increased incidence of autoimmune disease.

OBJECTIVE: It has been suggested that certain genetic risk factors indicative of an autoimmune mechanism can be identified in patients with inflammatory aortic aneurysm (IAA). We therefore investigated whether there was a higher incidence of autoimmune diseases in patients with IAA. Further, we explored risk factors, need for in-hospital resources, and early results of treatment, in a case-control study in a university hospital setting. Material and methods From 1983 to 1994, 520 patients were operated because of abdominal aortic aneurysm (AAA). Thirty-one patients had IAA. Control subjects were matched for aneurysm rupture, emergency or elective hospital admission, and date of operation. Two noninflammatory AAA were included for every IAA. RESULTS: Of the 31 patients with IAA, 6 patients (19%) had autoimmune disease, compared with none of the control subjects (P =.0017). Two patients had rheumatoid arthritis, 2 patients had systemic lupus erythematosus, 1 had giant cell arteritis, and 1 patient had an undifferentiated seronegative polyarthritis diagnosed as rheumatoid arthritis. Nineteen patients (61%) with IAA had involvement of the duodenum, and 8 patients (26%) had hydronephrosis with ureteral involvement. Operating time was longer in the IAA group, which also had a higher need for blood transfusion. Hospital stay, intensive care unit stay, and 30-day mortality were similar in the two groups. CONCLUSION: Except for longer operating time and more need for blood transfusions in the IAA group, use of hospital resources was similar after operations to treat IAA or noninflammatory AAA. The study findings indicate an association between IAA and autoimmune disease. This is in accordance with other reports that showed a genetic risk determinant mapped to the human leukocyte antigen (HLA) molecule in these patients. Further research is necessary to explore whether IAA might be a separate entity with a role of antigen binding in the origin of the disease.

Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons.

BACKGROUND: Hereditary hemochromatosis (HH) is a common genetic disease leading to accumulation of iron in several organs, most notably the liver. The C282Y/C282Y mutation in the HFE gene is found in most cases. In order to prevent clinical disease and to study the cost and feasibility of screening, a large population was screened. METHODS: In a Norwegian county, all inhabitants 20 years or older were invited to participate in a population-based health survey programme. Screening for HH was one of several subprojects. Blood samples were obtained from 65,238 persons. Subjects with high serum transferrin saturation in two tests and high serum ferritin were clinically evaluated for HH. All subjects with high serum transferrin saturation in two tests were offered genotyping. RESULTS: HH was newly diagnosed in 92 women and 177 men. Phlebotomy treatment was performed in 64 women and 152 men. Severe organ damage (liver cirrhosis) was ascertained in only 4 men. We found no correlation between serum ferritin and age. The estimated cost was US$ 1.6 per subject screened and US$ 390 per newly discovered HH subject. The estimated prevalence of phenotypical HH not previously known was 0.34% in women and 0.68% in men. The prevalence of the C282Y/C282Y mutation was at least 0.68%. CONCLUSION: Large-scale screening for HH can be performed at a relatively low cost if combined with a health survey programme. The yield in terms of newly discovered cases is considerable, but few cases were found seriously ill. Better knowledge of the natural course of HH is necessary if we are to be able to estimate the cost-effectiveness of large-scale screening.

Eosinophil counts and urinary eosinophil protein X in children hospitalized for wheezing during the first year of life: prediction of recurrent wheezing.

UNLABELLED: Early identification of wheezing children with an increased risk of recurrent wheezing or subsequent asthma is important. The aim of the study was to determine the role of markers of eosinophil activation, along with other parameters, in the prediction of recurrent wheezing and allergic sensitization in children with early and severe wheezing. We examined 105 children without atopic dermatitis, hospitalized for wheezing during the first year of life. At a 20-mo follow-up, 101 of the children were assessed for the occurrence of recurrent wheezing (at least 3 episodes, including 1 in the previous 6 mo) and allergic sensitization (positive skin-prick test). By univariate analysis, levels of eosinophil counts at the time of hospitalization (p = 0.005, OR = 18.9), age in months (p < 0.0001, OR = 1.5), respiratory syncytial virus (RSV)-negative disease (p < 0.0001, OR = 8.8), parental atopy (p = 0.006, OR = 3.3) and male sex (0.02, OR = 2.7) were all predictive factors for recurrent wheezing at follow-up. With all parameters included in a multiple regression analysis, RSV-negative disease was not a predictive factor for recurrent wheezing. A simple model including eosinophil counts > or = 0.1 x 10(9)/L and age had a predictive accuracy of 79%, with only a 6% chance of a child being wrongly predicted as symptomatic. Urinary protein X (U-EPX) was not a predictive factor for recurrent wheezing. When included in a multiple logistic regression analysis, a level of U-EPX > or = 100 microg/mmol creatinine was the only parameter with a positive predictive value for allergic sensitization (p = 0.007, OR = 18.9), whereas age, parental allergy or parental asthma were not. CONCLUSION: Children with severe wheezing during the first year of life and subsequent recurrent wheezing are characterized by a normal or high eosinophil count in response to viral infections.

Reduction of extraction times in liquid-phase microextraction.

Recently, we introduced a simple and inexpensive disposable device for liquid-phase microextraction (LPME) based on porous polypropylene hollow fibres. In the present paper, extraction times were significantly reduced by an increase in the surface of the hollow fibres. The model compounds methamphetamine and citalopram, were extracted from 2.5 ml of urine, plasma, and whole blood after dilution with water and alkalisation with 125 microl of 2 M NaOH though a porous polypropylene hollow fibre impregnated with hexyl ether and into an aqueous acceptor phase consisting of 0.1 M HCl. Two commercially available hollow fibres, which differed in surface area, wall thickness and internal diameter, were compared. An increase in the contact area of the hollow fibre with the sample solution by a factor of approximately two resulted in reduction in equilibrium times by approximately the same factor. Thus, the model compounds were extracted to equilibrium within 15 min from both urine and plasma, and within 30 min from whole blood. For the first time LPME was utilised to extract drugs from whole blood, and the extracts were comparable with plasma both with regard to sample clean-up and extraction recoveries. Extraction recoveries for methamphetamine and citalopram varied from 60 to 100% using the two fibres and the different matrices.

Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression.

Ataxia-telangiectasia (A-T) is an autosomal recessive disease characterized by progressive cerebellar degeneration, immunodeficiencies, genomic instability and gonadal atrophy. A-T patients are hypersensitive to ionizing radiation and have an elevated cancer risk. Cells derived from A-T patients require higher levels of serum factors, exhibit cytoskeletal defects and undergo premature senescence in culture. We show here that expression of the catalytic subunit of telomerase (hTERT) in primary A-T patient fibroblasts can rescue the premature senescence phenotype. Ectopic expression of hTERT does not rescue the radiosensitivity or the telomere fusions in A-T fibroblasts. The hTERT+AT cells also retain the characteristic defects in cell-cycle checkpoints, and show increased chromosome damage before and after ionizing radiation. Although A-T patients have an increased susceptibility to cancer, the expression of hTERT in A-T fibroblasts does not stimulate malignant transformation. These immortalized A-T cells provide a more stable cell system to investigate the molecular mechanisms underlying the cellular phenotypes of Ataxia-telangiectasia.

Neuroendocrine differentiation in bronchial carcinomas of classic squamous-cell type: an immunohistochemical study of 29 cases applying the tyramide signal amplification technique.

With regard to the cellular origin of bronchial squamous-cell carcinomas, there are some clinicopathologic and experimental data indicating a link between neuroendocrine (NE) bronchial tumors and the traditionally non-NE squamous-cell carcinomas. Against this background, 29 consecutively resected bronchial squamous-cell carcinomas were examined immunohistochemically (IHC) by means of the specific NE cell marker chromogranin A (CgA), using not only conventional IHC methods, but also the technique with increased sensitivity, offered by the tyramide signal amplification (TSA) procedure. Whereas none of the 29 tumors displayed CgA immunoreactive (IR) cells using the conventional IHC procedure, 10 were found to display a fine granular CgA IR in the neoplastic parenchymal cells using the TSA technique. This incidence is higher than previously reported. However, the CgA IR cells never formed any majority cell population of the neoplastic parenchyma; when present, most of them occurred as micronodules or larger confluent areas in the peripheral most undifferentiated parts of the carcinomatous sheets. Single CgA IR cells were detected only rarely in the spinocellular or keratinized areas. It can be speculated that the observations conform with the recently proposed hypothesis that there is a reservoir of NE progenitor cells in the bronchial mucosa capable of proliferation.

Liquid-phase microextraction and capillary electrophoresis of citalopram, an antidepressant drug.

A newly developed disposable device for liquid-phase microextraction (LPME) was evaluated for the capillary electrophoresis (CE) of the antidepressant drug citalopram (CIT) and its main metabolite N-desmethylcitalopram (DCIT) in human plasma. CIT and DCIT were extracted from 1 ml plasma samples through hexyl ether immobilised in the pores of a porous polypropylene hollow fibre and into 25 microl of 20 mM phosphate buffer (pH 2.75) present inside the hollow fibre (acceptor phase). Prior to extraction, the samples were made strongly alkaline in order to promote LPME of the basic drugs. Owing to the high ratio between the volumes of sample and acceptor phase, and owing to high partition coefficients, CIT and DCIT were enriched by a factor of 25 to 30. In addition, sample clean-up occurred during LPME since salts, proteins and the majority of endogenic substances were unable to penetrate the hexyl ether layer. Since the extracts were aqueous, they were injected directly into the CE instrument. Limits of quantification (S/N= 10) for CIT and DCIT in plasma were 16.5 ng/ml and 18 ng/ml respectively, while the limits of detection (S/N=3) were 5 ng/ml and 5.5 ng/ml respectively. This enabled CIT (and DCIT) to be analysed within the therapeutic range by LPME-CE and detection limits were comparable with previously reported HPLC methods.

Beta-cell differentiation from a human pancreatic cell line in vitro and in vivo.

Cell transplantation therapy for diabetes is limited by an inadequate supply of cells exhibiting glucose-responsive insulin secretion. To generate an unlimited supply of human beta-cells, inducibly transformed pancreatic beta-cell lines have been created by expression of dominant oncogenes. The cell lines grow indefinitely but lose differentiated function. Induction of beta-cell differentiation was achieved by stimulating the signaling pathways downstream of the transcription factor PDX-1, cell-cell contact, and the glucagon-like peptide (GLP-1) receptor. Synergistic activation of those pathways resulted in differentiation into functional beta-cells exhibiting glucose-responsive insulin secretion in vitro. Both oncogene-expressing and oncogene-deleted cells were transplanted into nude mice and found to exhibit glucose-responsive insulin secretion in vivo. The ability to grow unlimited quantities of human beta-cells is a major step toward developing a cell transplantation therapy for diabetes.

Diabetes mellitus-cell transplantation and gene therapy approaches.

Diabetes mellitus affects millions of people in the United States and worldwide. It has become clear over the past decade that the chronic complications of diabetes result from lack of proper blood glucose concentration regulation, and particularly the toxic effects of chronic hyperglycemia on organs and tissues. Pancreas transplants can cure insulin-dependent diabetes mellitus (IDDM). Furthermore, recent advances in pancreatic islet isolation and immunosuppressive regimens have resulted in dramatic improvements in the survival and function of islet allografts. Therefore, islet replacement strategies are becoming increasingly attractive options for patients at risk for severe diabetic complications. A major limitation of these approaches is the small number of organs available for transplantation or islet isolation. Thus, an important next step in developing curative treatments for type I diabetes will be the generation of a replenishable source of glucose-responsive, insulin-secreting cells that can be used for beta cell replacement. This review focuses on approaches to developing robust and widely applicable beta-cell replacement strategies with an emphasis on manipulating beta-cell growth and differentiation by genetic engineering.

Primary treatment of cervical carcinoma. Ten years experience from one Norwegian health region.

OBJECTIVE: To study the primary care of cervical carcinoma with regard to clinical and pathological factors, treatment decisions, complications and survival. DESIGN: A historical cohort comprising all women hospitalized with invasive cervical carcinoma (n=293) during the period 1987-1996. RESULTS: Median age was 52 years (range 23-90). FIGO stage distribution was 62%, 15%, 18% and 5% in stages I, II, III and IV, respectively. Early stage disease correlated with young age. Histologic types were: squamous cell carcinoma 84%, adenocarcinoma 11%, adenosquamous carcinoma 4% and small cell/anaplastic carcinoma 1%. Primary therapies were: surgery 188 women (64%), radiotherapy 99 women (34%), chemotherapy two women (0.7%); four women not treated (1.3%). Complications after surgery in 25 women (13%), none were fatal. Acute or late complications after primary or postoperative radiotherapy in 39 women (25%), seven (4.6%) were late serious complications. Three women died from complications related to radiotherapy. Mean follow-up of surviving patients was 58 months. Overall disease specific five-year survival was 70%. Five-year survival in stages IA, IB, II and III was 100%, 88%, 58% and 20%, respectively. One-year survival in stage IV was 31%. Median survival in stages III and IV according to curative or palliative aim of treatment was 20 and 6 months, respectively (p<0.005). CONCLUSION: Satisfactory quality of diagnosis and therapy have been maintained through regional care for cervical cancer patients.

[Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy]. / Polycystisk lipomembranøs osteodysplasi med skleroserende leukoencefalopati.

BACKGROUND: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu-Hakola syndrome) (PLO-SL) is an unusual cause of early dementia in which the decline in cognitive function is associated with multiple bone cysts, in particular in hands and feet. About 165 cases of this autosomal recessive hereditary disease have been reported worldwide, mostly from Finland and Japan. MATERIAL AND METHODS: In this article, case histories of PLO-SL are presented of two brothers who were born to consanguineous parents on an island outside the western coast of Norway. They are the 3rd and 4th patients in Norway described with this disorder. RESULTS: One of the brothers was diagnosed retrospectively and the diagnosis was not made in the other even when he had fractures without entirely adequate trauma. INTERPRETATION: It is suspected that the disease is underdiagnosed. For this reason, all patients with polycystic lesions in the skeleton should be evaluated for their mental state and all patients with an etiologically unclear dementia before the age of 50 should be investigated with x-rays of hands and/or feet.

Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro.

Widespread application of beta-cell replacement strategies for diabetes is dependent upon the availability of an unlimited supply of cells exhibiting appropriate glucose-responsive insulin secretion. Therefore, a great deal of effort has been focused on understanding the factors that control beta-cell growth. Previously, we found that human beta-cell-enriched islet cultures can be stimulated to proliferate, but expansion was limited by growth arrest after 10-15 cell divisions. Here, we have investigated the mechanism behind the growth arrest. Our studies, including analyses of the expression of senescence-associated beta-galactosidase, p16(INK4a) levels, and telomere lengths, indicate that cellular senescence is responsible for limiting the number of cell divisions that human beta-cells can undergo. The senescent phenotype was not prevented by retroviral transduction of the hTERT gene, although telomerase activity was induced. These results have implications for the use of primary human islet cells in cell transplantation therapies for diabetes.

[Bad shots--skin and soft tissue infections following intravenous drug abuse]. / Bomskudd--hud- og bløtdelsinfeksjoner i forbindelse med injeksjonsmisbruk.

Infection at the injection site following parenteral drug abuse is a well known complication. In Oslo, Norway's capital city with a population of 500,000, most of these infections are treated on an out-patient basis in the surgical department at Oslo Legevakt, a publicly funded primary health care facility. During the four last months of 1998, 179 patients were admitted with skin and soft tissue infections at the injection site compared to only 46 in the same period in 1993. This suggests that the problem is increasing. In this retrospective study these populations were analysed according to their age, sex, clinical appearance, and the treatment given. In 1998, 36 patients were admitted to hospital, the rest treated on an out-patient basis. A total of 112 patients were treated with simple incision and drainage, 63 of whom were given antibiotics. 37 patients were treated with antibiotics only. There were few complications; two patients with deep venous thrombosis and one in need of skin transplantation. We saw no development of life threatening infections among our patients. The article also gives suggestions for treatment.

Liquid-liquid extraction procedures for sample enrichment in capillary zone electrophoresis.

This review article presents an overview of applications of liquid-liquid extraction (LLE) for analyte enrichment and clean-up of samples prior to capillary zone electrophoresis (CZE). The basic principles of LLE are discussed with special emphasis on analyte enrichment. In addition, attention is focused on the requirements for the final extract to be compatible with CZE. The paper discusses selected examples from the literature with special emphasis on detection limits in drug analysis and in environmental chemistry. Finally, the paper focus on alternative liquid-phase extraction concepts based on electroextraction, supported liquid membranes, and liquid-phase microextraction.