Similar birthweight in children born to HIV-2 infected and HIV-negative women in Guinea-Bissau.
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Adult↗
Biomedical subjects
S Andersson
Publications and source records attributed to S Andersson.
Mechanisms of diarrhoea in myotonic dystrophy.
BACKGROUND: Gastrointestinal (GI) symptoms are common in myotonic dystrophy (MD). Diarrhoea is one of the more disabling of these GI complaints. The mechanisms behind diarrhoea in MD have not previously been investigated systematically. OBJECTIVE: To elucidate the mechanisms behind diarrhoea in MD. METHODS: Twenty patients with MD and suffering from diarrhoea were investigated in order to detect malabsorption (blood tests and faecal fat excretion) and bile acid malabsorption ([75Se]selenahomocholic acid-taurine (SeHCAT) retention) and to study intestinal morphology (duodenal and rectal biopsies). RESULTS: Two patients had deficiency of folic acid and four showed reduced levels of pancreatic isoamylase, but none of them had steatorrhoea. Two out of eight patients had abnormal bile acid breath tests with normal SeHCAT, indicating small bowel bacterial overgrowth and 12 displayed reduced SeHCAT retention. Duodenal biopsies were normal in eight patients and five out of nine rectal biopsies displayed slight inflammation. CONCLUSIONS: A possible mechanism of diarrhoea in MD could be identified in most of the patients. Bile acid malabsorption seems to be a frequent cause and can be treated successfully.
Adult↗
Bronchoalveolar lavage with KL4-surfactant in models of meconium aspiration syndrome.
As a model of the meconium aspiration syndrome (MAS) of human infants, adult rabbits and newborn rhesus monkeys received intratracheal instillation of human meconium to induce pulmonary injury. Injured rabbits were ventilated with 100% O2 and divided into four treatment groups, receiving: 1) bronchoalveolar lavages (BAL) with dilute KL4-Surfactant; 2) lavages with equal volumes of sterile saline; 3) a single intratracheal bolus of KL4-Surfactant, 100 mg/kg; and 4) no treatment. The untreated rabbits developed atelectasis, a fall in pressure-volume levels and in partial pressure of O2 in arterial blood (PaO2) from approximately 500 to < 100 mm Hg, and severe pulmonary inflammation between 3 and 5 h after instillation of meconium. Rabbits treated by BAL with dilute KL4-Surfactant showed rapid and sustained recovery of PaO2 to approximately 300 mm Hg within minutes, a return toward normal pressure-volume levels, and diminished inflammation. Rabbits receiving BAL with saline failed to show recovery, and rabbits treated with a bolus of surfactant intratracheally exhibited a transient response by 1-2 h after treatment, but then returned to the initial atelectatic state. Newborn rhesus monkeys, after receiving human meconium intratracheally before the first breath, developed severe loss of pulmonary function. Treatment of these monkeys 1-5 h after birth with BAL with dilute KL4-Surfactant produced clearing of chest radiographs and a rapid improvement in pulmonary function with ratios of partial pressure of O2 in arterial blood to the fraction of O2 in the inspired air rising into the normal range where they remained through the 20-h period of study. The studies indicate that pulmonary function in two models of severe meconium injury respond rapidly to BAL with dilute KL4-Surfactant.
Animals↗
17Beta-hydroxysteroid dehydrogenase types 1 and 2 in human placenta: an immunohistochemical study with correlation to placental development.
In estrogen metabolism, the enzymatic properties of the 17beta-hydroxysteroid dehydrogenase (17betaHSD) isozymes play very important roles in steroid hormone metabolism in various tissues, including the placenta. 17betaHSD type 1 catalyzes primarily the reduction of estrone (E1) to estradiol (E2), whereas 17betaHSD type 2 catalyzes primarily the oxidation of E2 to E1. In this study, we examined immunohistochemical localization of 17betaHSD types 1 and 2 in human placenta (31 cases) ranging from 4-40 weeks gestation. The immunoreactivity of 17betaHSD type 1 was exclusively detected in syncytiotrophoblast from 4 weeks gestation to term placenta. Immunoreactivity of 17betaHSD type 2 first appeared in endothelial cells of intravillous vessels at 12 weeks gestation, and the number of 17betaHSD type 2-positive endothelial cells markedly increased up to 19 weeks, then reached a plateau. We quantitatively evaluated the 17betaHSD type 2-positive endothelial cells in chorionic villi and determined the ratio of 17betaHSD type 2-positive endothelial cells using immunohistochemistry of CD34, an endothelial antigen, in serial mirror tissue sections and subsequent image analysis using CAS 200. CD34 was detected from 4 weeks gestation, and its positive areas continued to increase toward term. The 17betaHSD type 2-positive area per CD34-positive area markedly increased from 13 weeks gestation and reached a plateau at 19 weeks gestation, in which almost all endothelial cells were positive for 17betaHSD type 2. 17BetaHSD type 2, therefore, is considered to prevent the passage of excessive estrogens into the fetal circulation at endothelial cells of the intravillous fetal capillaries by catalyzing the inactivation ofE2 to E1.
17-Hydroxysteroid Dehydrogenases↗
Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol.
Aberrant aromatase expression in stromal cells of endometriosis gives rise to conversion of circulating androstenedione to estrone in this tissue, whereas aromatase expression is absent in the eutopic endometrium. In this study, we initially demonstrated by Northern blotting transcripts of the reductive 17beta-hydroxysteroid dehydrogenase (17betaHSD) type 1, which catalyzes the conversion of estrone to 17beta-estradiol, in both eutopic endometrium and endometriosis. Thus, it follows that the product of the aromatase reaction, namely estrone, that is weakly estrogenic can be converted to the potent estrogen, 17beta-estradiol, in endometriotic tissues. It was previously demonstrated that progesterone stimulates the inactivation of 17beta-estradiol through conversion to estrone in eutopic endometrial epithelial cells. Subsequently, 17betaHSD type 2 was shown to catalyze this reaction, and its transcripts were detected in the epithelial cell component of the eutopic endometrium in secretory phase. Because 17beta-estradiol plays a critical role in the development and growth of endometriosis, we studied 17betaHSD-2 expression in endometriotic tissues and eutopic endometrium. We demonstrated, by Northern blotting, 17betaHSD-2 messenger ribonucleic acid (RNA) in all RNA samples of secretory eutopic endometrium (n=12) but not in secretory samples of endometriotic lesions (n=10), including paired samples of endometrium and endometriosis obtained simultaneously from eight patients. This messenger RNA was not detectable in any samples of proliferative eutopic endometrium or endometriosis (n=4) as expected. Next, we confirmed these findings by demonstration of immunoreactive 17betaHSD-2 in epithelial cells of secretory eutopic endometrium in 11 of 13 samples employing a monoclonal antibody against 17betaHSD-2, whereas 17betaHSD-2 was absent in paired secretory endometriotic tissues (n=4). Proliferative eutopic endometrial (n=8) and endometriotic (n=4) tissues were both negative for immunoreactive 17betaHSD-2, except for barely detectable levels in 1 eutopic endometrial sample. Finally, we sought to determine whether deficient 17betaHSD-2 expression in endometriotic tissues is due to impaired progesterone action in endometriosis. We determined by immunohistochemistry the expression of progesterone and estrogen receptors in these paired samples of secretory (n=4) and proliferative (n=4) eutopic endometrium and endometriosis, and no differences could be demonstrated. In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone. The lack of 17betaHSD-2 expression in endometriosis is not due to alterations in the levels of immunoreactive progesterone or estrogen receptors in this tissue and may be related to an inhibitory aberration in the signaling pathway that regulates 17betaHSD-2 expression.
17-Hydroxysteroid Dehydrogenases↗
Deleterious missense mutations and silent polymorphism in the human 17beta-hydroxysteroid dehydrogenase 3 gene (HSD17B3).
Isozymes of 17beta-hydroxysteroid dehydrogenase (17betaHSD) regulate levels of bioactive androgens and estrogens in a variety of tissues. For example, the 17betaHSD type 3 isozyme catalyzes the conversion of the inactive C19-steroid androstenedione to the biologically active androgen, testosterone, in the testis. Testosterone is essential for the correct development of male internal and external genitalia; hence, deleterious mutations in the HSD17B3 gene give rise to a rare form of male pseudohermaphroditism termed 17betaHSD deficiency. Here, 2 additional missense mutations in the HSD17B3 gene in subjects with 17betaHSD deficiency are described. One mutation (A56T) impairs enzyme function by affecting NADPH cofactor binding. A second mutation (N130S) led to complete loss of enzyme activity. Also, a single base pair polymorphism in exon 11 of the HSD17B3 gene is described. The polymorphic A allele encodes a protein with a serine rather than a glycine at position 289 (GGT --> AGT). The frequency of the G allele (Gly) was 0.94, and that of the A allele (Ser) was 0.06. No difference in the frequencies of the G and A alleles was detected in 32 apparently normal women and 46 women with polycystic ovary syndrome. Enzymes bearing either glycine or serine at this position have similar substrate specificities and kinetic constants. The current findings boost to 16 the number of mutations in the HSD17B3 gene that impair testosterone synthesis and cause male pseudohermaphroditism, and add 1 apparently silent polymorphism to this tally.
17-Hydroxysteroid Dehydrogenases↗
HIV-2 genetic variation and DNA load in asymptomatic carriers and AIDS cases in Guinea-Bissau.
The purpose of this study was to document which genetic subtypes of HIV-2 are present in Guinea-Bissau and to investigate whether asymptomatic HIV-2 carriers and AIDS patients carry distinct genetic variants. A secondary aim was to correlate proviral DNA load to clinical and immunologic status of the patients. Thirty-eight asymptomatic HIV-2 carriers and 11 AIDS patients from Bissau, Guinea-Bissau were included in a cross-sectional study in which HIV-2 env V3 sequences, HIV-2 DNA load, and CD4-positive (CD4+) lymphocyte counts were determined. Phylogenetic analyses showed that all investigated subjects carried subtype A HIV-2 variants and that the sequences from AIDS patients and asymptomatic carriers did not form distinct subclusters in the tree. As expected, patients with AIDS had significantly higher median HIV-2 DNA load than did asymptomatic carriers (4.6 vs. 2.0 log10 HIV-2 DNA copies/10(6) CD4+ lymphocytes). Our study indicates that the HIV-2 epidemic in Guinea-Bissau is almost exclusively caused by subtype A HIV-2 variants and that the HIV-2 infections among the asymptomatic carriers and AIDS cases included in the study do not have distinct epidemiologic histories.
Acquired Immunodeficiency Syndrome↗
Prevalence and risk factors for HTLV-II infection in 913 injecting drug users in Stockholm, 1994.
The prevalence and risk factors for acquisition of human T-cell lymphotropic virus type I and II (HTLV-I and II) were investigated in a prospective study of 913 injecting drug users (IDUs) in Stockholm in 1994. Epidemiologic data were recorded, and blood samples were tested for antibodies against HTLV-I and HTLV-II; human immunodeficiency virus (HIV) types 1 and 2; and hepatitis A (HAV), B (HBV), C (HCV), and D (HDV). Positive serologic results for HTLV were confirmed by Western blot (WB) and polymerase chain reaction (PCR). Of the 905 participants with conclusive HTLV-II status, 29 (3.2%) were HTLV-II positive, and all but three were of Nordic descent. None was HTLV-I infected. One person was infected as early as 1981, before HIV had reached the IDU population in Sweden. The prevalence of HTLV-II infection was 12% among HIV-1-seropositive and 1.8% among HIV-1-seronegative participants. The overall seroprevalences were 14% for HIV-1, 0% for HIV-2, 41% for HAV, 75% for HBV, 92% for HCV, and 8% for HDV. Although amphetamine has been the main injecting drug in Sweden for several decades, heroin abuse combined with a debut of injecting drugs before 1975 was identified as the most important risk factor associated with HTLV-II infection. HAV and HIV seropositivity were also independent risk factors.
Adult↗
HTLV-I and -II infections in a nationwide survey of pregnant women in Guinea-Bissau, West Africa.
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Female↗
Determination of total iodine in biological material by alkaline ashing and column-switching ion-pair liquid chromatography.
A method for the determination of total iodine in biological material has been developed. The method combines alkaline ashing with a selective and sensitive column-switching ion-pair HPLC technique. The ashing procedure which converts the organically bound iodine to iodide is miniaturised and requires only about 100 mg of sample. The first column of the column-switching system is polymer based and can therefore withstand the alkaline pH obtained after ashing. On the analytical column the iodide is separated as an ion-pair with tetrabutyl ammonium hydrogensulphate. The method has been applied to samples from whole blood, urine, liver, lung, carcass, and a sample throughput of at least 50 samples per day can be achieved. Validation studies by spiking experiments showed the precision to be better than 10% R.S.D. for all matrices with recoveries in the range 87-97%. The method has been applied for samples with an iodine content in the range 0.07-1060 microg/g.
Animals↗
[AIDS ravages in Africa].
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Acquired Immunodeficiency Syndrome↗
Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases.
17 beta-Hydroxysteroid dehydrogenases (17 beta-HSDs) are enzymes involved in both the activation and inactivation of androgens and estrogens. 17 beta-HSD type 1 shows a high specificity for C18 steroids and is the major isozyme in the granulosa cells of the ovary. Its role is to convert the inactive C18 steroid estrone to the active estrogen estradiol, which in turn locally promotes maturation of the follicle. In contrast, attenuation of estradiol action in the glandular epithelium of the secretory endometrium is achieved by expression of the oxidative type 2 isozyme that inactivates estradiol to estrone. An interesting feature of 17 beta-HSD type 2 is that the enzyme also possesses 20 alpha-HSD activity, i.e., it catalyzes the 20 alpha-oxidation of the inactive C21 steroid 20 alpha-dihydroprogesterone to the active progestin progesterone. As the type 2 enzyme is also active on androgens, it may play a general role in the peripheral inactivation of androgens and estrogens, thus determining their steady-state levels in target tissues. The reductive 17 beta-HSD type 3 is predominantly expressed in the testis and converts the inactive C19 steroid androstenedione to the active androgen testosterone. The importance of the type 3 enzyme in male steroid hormone physiology is underscored by the genetic disease 17 beta-HSD deficiency. Mutations in the 17 beta-HSD3 gene impair the formation of testosterone in the fetal testis and give rise to genetic males with normal male Wolffian duct structures but female external genitalia. To date, 15 mutations have been identified in 18 subjects with the disease.
17-Hydroxysteroid Dehydrogenases↗
Inhibition of rat alpha-reductases by finasteride: evidence for isozyme differences in the mechanism of inhibition.
The mechanism of inhibition of the rat types 1 and 2 5alpha-reductase by finasteride was investigated using recombinantly expressed enzymes. These studies revealed that finasteride is a potent, reversible inhibitor of the rat type 1 5alpha-reductase with Ki=10.2+/-1.3 nM. Finasteride is a potent inhibitor of the rat type 2; however, in this case the compound binds to the type 2 isozyme-NADPH complex to form a ternary complex with Ki=1.19+/-0.10 nM, which then rearranges to a high affinity complex (E:I) with a pseudo first order rate constant of 1.62+/-0.22 x 10(-3)/s. The second order rate constant is k3/Ki=1.37+/-0.31 x 10(6) M/s. Heat denaturation of the (type 2 enzyme:inhibitor) complex releases dihydrofinasteride and presumably the NADP+-adduct previously identified with the human 5alpha-reductases. The effects of finasteride were also studied in intact COS cells transiently expressing the rat types 1 and 2 5alpha-reductase. Results with whole cell assays confirm differences in mechanism of inhibition of rat types 1 and 2 5alpha-reductase by finasteride.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Field evaluation of alternative testing strategies for diagnosis and differentiation of HIV-1 and HIV-2 infections in an HIV-1 and HIV-2-prevalent area.
OBJECTIVE: To identify cost-efficient alternative antibody testing strategies for screening, confirmation and discrimination of HIV-1 and HIV-2 infections, including rapid simple tests (RST) as well as enzyme-linked immunosorbent assays (ELISA), in a HIV-1 and HIV-2-prevalent area. DESIGN: Evaluation and comparison of anti-HIV-1/2 assays, adhering to the World Health Organization recommendations for alternative confirmatory strategies, using banked and prospectively collected specimens in Guinea-Bissau. METHODS: A total of 1110 consecutive sera from Bissau were included in the first phase, of which 198 (17.8%) were HIV-seropositive: 52 (4.7%) HIV-1, 120 (10.8%) HIV-2, and 26 (2.3%) HIV-1/HIV-2 dually reactive. In addition, 95 selected HIV-positive specimens were included for study of sensitivity and cross-reactivity between HIV-1 and HIV-2. Western blot was used as a gold standard for confirming the reactivity of the specimens. All specimens were screened by two assays. Enzygnost ELISA and Capillus RST. Samples reactive by any of the screening assays were further tested by assays chosen for confirmation: UBI ELISA, Innotest ELISA Recombigen RST, Multispot RST and Immunocomb RST. The confirmatory RST as well as Wellcozyme Recombinant HIV-1 ELISA, PEPTI-LAV and INNO-LIA were also used to study differentiation between HIV-1 and HIV-2. RESULTS: The sensitivities of all assays were 100%. The specificities of the screening assays at initial and repeated testing were 98.0 and 99.7%, respectively, for Enzygnost and 99.8 and 99.9%, respectively, for Capillus. The various combinations of two or three assays showed specificities of 99.2-100%. Several possible combinations of assays were identified where a specificity of 100% and good differentiation between HIV-1 and HIV-2 was achieved. Significant differences in the capacity to discriminate were noted; Immunocomb and PEPTI-LAV had the lowest number of dual-reactive results. A follow-up study of 1501 consecutive samples tested with the strategy chosen for routine use showed a sensitivity and specificity comparable to ELISA and Western blot. CONCLUSION: High sensitivities and specificities were obtained with various combinations of assays including RST as well as ELISA, and these procedures are well suited for field use in Africa. Serodiagnostic strategies for HIV can be based on RST alone and differentiation between HIV-1 and HIV-2 can be achieved as part of these strategies. Large differences in the capacity of individual assays to discriminate between HIV-1 and HIV-2 were observed.
Diagnosis, Differential↗
Leptin concentration in cord blood correlates with intrauterine growth.
Leptin is an adipocyte-derived peptide hormone regulating energy balance in experimental animals. Although the physiological function of leptin in humans is still unclear, its secretion is closely related to fat mass in adult humans. To examine how fetal growth correlates with leptin levels at birth, an umbilical cord venous blood sample was obtained at the delivery from 50 term newborn infants. Twenty-eight of the newborn infants had birth weights appropriate for gestational age (AGA; mean +/- SEM, 3362 +/- 90 g; relative birth weight, -0.08 +/- 0.2 SD), 9 were large for gestational age (birth weight, 4655 +/- 165 g; relative birth weight, 3.2 +/- 0.3 SD; P < 0.001 vs. AGA newborn infants), and 13 were small for gestational age (SGA; birth weight, 2385 +/- 69 g; relative birth weight, -2.2 +/- 0.08 SD; P < 0.001 vs. AGA newborn infants). Leptin concentrations were higher in large for gestational age (35.7 +/- 8.0 micrograms/L; P < 0.005), but lower in SGA (3.3 +/- 0.5 micrograms/L; P < 0.001) than in AGA infants (14.5 +/- 2.8 micrograms/L). When adjusted for differences in body weight, mean leptin levels were similar in the three newborn groups. Leptin concentration correlated closely with both absolute and relative birth weights (r = 0.71; P < 0.001 in both), with cord blood insulin concentration (r = 0.67; P < 0.001), and with placental weight (r = 0.60; P < 0.001). These data suggest that leptin is synthesized in utero, and that the circulating leptin concentration relates to the intrauterine growth pattern.
Amniotic Fluid↗
Cell type-specific expression of 17 beta-hydroxysteroid dehydrogenase type 2 in human placenta and fetal liver.
The enzymatic actions of the 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) isozymes are crucial in steroid hormone metabolism/physiology. The type 1 isozyme catalyzes the conversion of the biologically inactive C18 steroid, estrone, to the active estrogen, 17 beta-estradiol, and the enzyme is predominantly expressed in the syncytiotrophoblast of the placenta and the granulosa cells of the ovary. 17 beta HSD type 2 is highly expressed in placenta, liver, and secretory endometrium and catalyzes the conversion of bioactive estrogens and androgens to biologically inactive 17-ketosteroid counterparts. The expression pattern of 17 beta HSD type 2 protein was determined in human term placenta and fetal liver by immunohistochemical analysis using monoclonal antibodies directed against distinct epitopes of the 17 beta HSD type 2 protein. In placenta, the protein was detected in the endothelial cells of fetal capillaries, but not in cytotrophoblasts or syncytiotrophoblast. There was dichotomous immunostaining seen among pairs of cotyledonary vessels and chorionic vessels. In the liver, on the other hand, staining was detected in the hepatocytes, but not in the cells lining blood vessels. We conclude that the cell type-specific localization of 17 beta HSD type 2 is in accord with the proposed physiological role of the enzyme, namely to protect tissues, in this case the fetus, from bioactive estrogen and androgen.
17-Hydroxysteroid Dehydrogenases↗
Differential gene expression of steroid 5 alpha-reductase 2 in core needle biopsies from malignant and benign prostatic tissue.
Androgens are implicated in the development of prostate cancer (CAP) and benign prostate hyperplasia. The conversion of testosterone to the more potent metabolite dihydrotestosterone by prostatespecific steroid 5 alpha-reductase type 2 (5 alpha-red2) is a key mechanism in the action of androgens in the prostate and is important in the promotion and progression of prostate diseases. Manipulation of the turnover of androgens is thus fundamental in the pharmacological treatment strategy. We have developed a sensitive solution hybridization method for quantification of the gene expression of 5 alpha-red2 in core needle biopsies of the prostate. The 5 alpha-red2-specific messenger RNA (mRNA) levels were measured in 50 human prostate transrectal ultrasound-guided core biopsies obtained from 31 outpatients (median age 72, range 67-88 yr) undergoing biopsy for diagnostic purposes. Significant differences were observed in the gene expression of 5 alpha-red2 between cancerous and noncancerous tissue. In the 14 biopsies judged cancerous, the median 5 alpha-red mRNA levels were 3.5 amol/ng total RNA compared with 12.0 amol/ng total RNA in the biopsies showing no cancer (P = 0.0018). The median 5 alpha-red2 mRNA level in noncancerous tissue was thus 3.4 times higher than in the cancerous specimens.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
High endothelin-1 in the airways of preterm infants is associated with less severe respiratory distress during the early postnatal period.
OBJECTIVE: To study the relationship between endothelin-1 (ET-1) in the airways and respiratory distress in preterm infants. METHODS: ET-1 was determined in 60 tracheal aspirates from 11 preterm intubated infants (gestational age 28.0 +/- 2.5 weeks) during the first week of life. RESULTS: The concentration of ET-1 of the aspirates was 6 to 2760 pg/mL (median 293 pg/mL). Negative correlations existed between mean log ET-1 and mean airway pressure (R2 = .812) and fraction of inspired oxygen (R2 = .591), whereas a positive correlation was found between the arteriolar/alveolar oxygenation ratio within 3 hours of birth and mean log ET-1 on the first day (R2 = .555). CONCLUSION: The association of high ET-1 in the airways with less severe respiratory distress in the early postnatal period may be attributable to effects of ET-1 on surfactant secretion or development of airway epithelium.
Endothelin-1↗