Chorioamnionitis induced by subchorionic endotoxin infusion in sheep

OBJECTIVE: This study was undertaken to determine whether subchorionic endotoxin infusion causes chorioamnionitis and preterm lung maturation, as occurs after intra-amniotic endotoxin. STUDY DESIGN: From day 118 of pregnancy, sheep received infusions of endotoxin (subchorionic 7.5 mg/d, n=11; intra-amniotic 2.5 mg/d, n=9) until delivery of lambs at 120 or 124 days. Other sheep received a single intra-amniotic injection of endotoxin (10 mg, n=7) at 118 days before delivery at 124 days. Controls (n=9) received equivalent saline solution treatments. RESULTS: Chorioamnionitis accompanied all endotoxin treatments. Lung inflammation occurred after intra-amniotic endotoxin infusion or injection but not after subchorionic endotoxin. Umbilical arterial pH was lower and Pco(2) was higher than control after subchorionic endotoxin. Lung compliance and surfactant were increased after intra-amniotic endotoxin infusion or injection but not after subchorionic endotoxin. CONCLUSION: Chorioamnionitis may result from inflammatory stimuli at various intrauterine sites, with different sites causing different fetal effects and not all cases of chorioamnionitis being accompanied by enhanced lung maturation.     

Betamethasone effects on chorioamnionitis induced by intra-amniotic endotoxin in sheep

OBJECTIVE: Intra-amniotic administration of endotoxin in sheep is a model of subclinical chorioamnionitis. Intrauterine inflammation alters lung development to improve postnatal lung function and may predispose the infant to lung and brain injury. We describe the effects of intra-amniotic endotoxin on cytokines and white cell responses in the membranes and amniotic fluid and investigate the hypothesis that betamethasone treatment suppresses these responses. STUDY DESIGN: Pregnant ewes were allocated at random to receive either intra-amniotic saline solution (control animals), maternal intramuscular betamethasone, intra-amniotic endotoxin by ultrasound guidance (10 mg Escherichia coli 055:B5), or a combination of the betamethasone and endotoxin treatments. Lambs were delivered abdominally at 110 to 125 days of gestation at time points that ranged from 2 hours to 15 days after treatment. RESULTS: When compared with saline solution-injected control animals, the intra-amniotic injection of endotoxin increased white cell counts in amniotic fluid. Levels of interleukin-8, but not interleukin-6, were significantly increased in amniotic fluid from 5 hours to 15 days after intra-amniotic endotoxin injection, and interleukin-8 levels were not decreased by concurrent treatment with betamethasone. After endotoxin treatment, interleukin-1beta and interleukin-8 messenger RNA were expressed in chorion, and interleukin-6 messenger RNA expression was localized to chorionic blood vessel epithelium. The half-life of endotoxin in the amniotic fluid was 1.7 days, and levels remained measurable 15 days after injection. CONCLUSION: These findings confirm that the fetus can survive within amniotic fluid that contains endotoxin, white cells, and cytokines for periods of weeks or more. Betamethasone treatment can suppress the initial inflammation in the amnion-chorion, but interleukin-8 levels and inflammatory cells in amniotic fluid were not suppressed 5 and 15 days after betamethasone treatment, presumably because of the slow clearance of bioactive endotoxin from the amniotic fluid.     

An XY female with Müllerian duct development and persistent Wolffian duct structures

Disorders of sexual differentiation are usually diagnosed at an early age. We hereby describe a case of a 29-year-old phenotypic woman who during the evaluation of amenorrhea was found to have a 46, XY karyotype. Further evaluation (including laparoscopy) suggested that she presented a variant of gonadal dysgenesis, with the particularity of having well-developed müllerian structures and testicular remnants alongside a steroid-producing gonadoblastoma.     

Intra-amniotic endotoxin induces lung maturation by direct effects on the developing respiratory tract in preterm sheep

OBJECTIVE: Our purpose was to determine whether improved preterm lung function caused by intraamniotic endotoxin treatment requires endotoxin entry into the respiratory tract. STUDY DESIGN: We assessed lung inflammation 2 days after intra-amniotic endotoxin (10 mg, Escherichia coli 055:B5) or saline solution in preterm lambs (123 days' gestation) that had undergone surgery to isolate the gastrointestinal or respiratory systems from the amniotic sac. In other sheep longer-term effects were assessed 7 days after we isolated the fetal respiratory tract and gave endotoxin or saline solution directly to the lungs or into the amniotic sac. We measured pulmonary inflammation, lung function, and surfactant 1 week after treatment (approximately 125 days). RESULTS: Pulmonary inflammation was present after intra-amniotic endotoxin only if there was communication between the respiratory tract and the amniotic sac. Lung function was improved and surfactant was increased only in preterm lambs that received direct pulmonary endotoxin. CONCLUSION: Endotoxin causes functional improvement of the preterm lung by direct effects on the developing respiratory system.     

The role of human glandular kallikrein 2 for prediction of pathologically organ confined prostate cancer

BACKGROUND: In recent studies serum levels of human glandular kallikrein 2 (hK2) demonstrated significant differences in pathologically organ-confined versus non-organ-confined prostate cancer (PCa). In this study we investigated whether hK2 adds independent information when considered together with traditionally used parameters to predict organ confined (pT2a/b) PCa. METHODS: Serum levels of hK2, total and free prostate-specific antigens (PSA) were obtained one day before radical prostatectomy in 245 consecutive men. These were included with clinical stage and biopsy Gleason grade into univariate analysis and multivariate logistic regression models. RESULTS: pT2a/b PCa was found in n = 148 patients. In univariate analysis all preoperative parameters demonstrated significant association with the presence of pT2a/b PCa. Using multivariate logistic regression model hK2 (P = 0.022), clinical stage (P < 0.0001), and Gleason grade (P < 0.0001) were independent predictors of pT2a/b PCa whereas PSA (P = 0.3) was not. In bootstrap corrected logistic regression based nomograms the addition of hK2 density marginally enhanced predictive accuracy when PSA, PSA density, clinical stage, and Gleason grade were considered (AUC = 0.879 without hK2 density and 0.883 with hK2 density). CONCLUSIONS: hK2 and hK2 density could independently predict pT2a/b PCa. However, improvement in predictive accuracy was marginal when nomograms based on traditional variables were complemented with this serum marker.     

HLAmatchmaker: a molecularly based algorithm for histocompatibility determination. III. Effect of matching at the HLA-A,B amino acid triplet level on kidney transplant survival

BACKGROUND: HLAMatchmaker is a recently developed computer-based algorithm to determine donor-recipient HLA compatibility at the molecular level. Originally designed for highly alloimmunized patients, this algorithm is based on the concept that immunogenic epitopes are represented by amino acid triplets on exposed parts of protein sequences of HLA-A, -B, and -C chains accessible to alloantibodies. Donor HLA compatibility is determined by intralocus and interlocus comparisons of triplets in polymorphic sequence positions. For most patients, HLAMatchmaker can identify certain mismatched HLA antigens that are zero-triplet mismatches to the patient's HLA phenotype and should, therefore, be considered fully histocompatible. The present study was designed to determine how class I HLA matching at the triplet level affects kidney transplant outcome. METHODS: We analyzed two multicenter databases of zero-HLA-DR-mismatched kidneys transplanted from 1987 to 1999. One database consisted of 31,879 primary allografts registered by U.S. transplant centers in the United Network for Organ Sharing database and the other consisted of 15,872 transplants in the Eurotransplant program. RESULTS: HLA-A,B mismatched kidneys that were compatible at the triplet level exhibited almost identical graft survival rates as the zero-HLA-A,B antigen mismatches defined by conventional criteria. This beneficial effect of triplet matching was seen for both nonsensitized and sensitized patients and also for white and nonwhite patients. CONCLUSIONS: These findings suggest that the application of HLAMatchmaker will increase the number of successful transplants, at least in the HLA-DR match combinations.     

Differential immunogenicity of HLA mismatches: HLA-A2 versus HLA-A28

The immunogenicity of human leukocyte antigen (HLA)-A2 versus HLA-A28 was analyzed by antibody production, cytotoxic T-lymphocyte (CTL) induction, and graft survival. We observed that an HLA-A2 mismatched child in HLA-A28 women leads to HLA-A2 specific antibodies in 32% of the women (n=31), whereas in the case of an HLA-A28 child and HLA-A2 women (n=30), no HLA-A28 specific antibodies were found ( P<0.002). Also, the CTL precursor frequencies were significantly lower against HLA-A28 compared with CTLp frequencies against HLA-A2 ( P=0.012). Finally, the kidney graft survival was slightly better in HLA-A2 positive recipients transplanted with HLA-A28 mismatches. We can conclude that single HLA-A28 mismatches are less immunogenic in HLA-A2 individuals compared with single HLA-A2 mismatches in HLA-A28 individuals, which is probably because the mismatched epitopes on the HLA-A2 molecule are unique epitopes, whereas the mismatched epitopes on HLA-A28 are shared by other HLA-A and HLA-B molecules.     

Merkel cell carcinoma: report of seven cases

Merkel cell carcinoma (MCC) is an infrequent, highly malignant, primary skin tumor derived from neuroendocrine cells. Most MCCs occur in elderly individuals, on sun-exposed areas of the body, with the head and neck being the most common sites. We present 7 patients (2 male and 5 female, age 45-80 years) suffering from MCC and treated between 1993 and 2000. All tumors were located on the head and neck and varied from 0.9 to 2.3 cm in size. Five of the patients had stage II disease, 1 patient had stage Ia disease and 1 patient had stage III disease. Six of the patients had positive regional lymph nodes. All patients had local excision of the tumor. Six of them also had lymph node dissection and in 5 of them a superficial parotidectomy was performed. Five patients received adjuvant radiotherapy and 3 of them also received chemotherapy. Local and cervical lymph node recurrence was observed in only 1 patient. Metastases occurred in 5 patients. One patient died within 10 days for other reasons. The patient with the stage III tumor had a survival of 7 months. The other 5 patients had survivals varying from 15 to 54 months. MCC is a skin tumor with very poor prognosis and high recurrence and metastatic rates. Its treatment is still under discussion. Radical excision of the tumor is the main method of treatment. Selective lymph node dissection is suggested. Superficial parotidectomy seems necessary, especially if the tumor is on the auricle. Adjuvant radio- and chemotherapy may extend survival in case of small-size tumors.     

The problem of predicting food intake during the period of adaptation to a new food: a model

A model is described which aims to predict intake immediately following a change from one food to another that is higher in bulk content; it deals with the transition from one 'equilibrium' intake to another. The system considered is an immature pig fed ad libitum on a single homogeneous food, which is balanced for nutrients and contains no toxins so that the first limiting resource is always energy. It is assumed that an animal has a desired rate of food intake (DFI) which is that needed to meet the energy requirements for protein and lipid deposition and for maintenance. DFI may not be achieved if a bulk constraint to intake exists. Where a bulk constraint operates intake is calculated as constrained food intake (CFI) where (where WHC is the water-holding capacity of the food (kg water/kg dry food) and Cwhc is the animal's capacity for WHC (units/kg live weight per d)). Where intake is not constrained it is assumed that genetic potential will be achieved. Potential growth rate is described by the Gompertz growth function. Where intake is constrained, growth will be less than the potential. Constrained growth rate is predicted as where W is pig weight (kg), EI is energy intake (MJ/d), Em is the energy required for maintenance (MJ/d) and eg is the energy required for unit gain (MJ/kg). The value of eg depends on weight and the fattening characteristics of the pig. Actual growth is predicted to be the lesser of potential and constrained growth. To deal with adaptation it is assumed that the time taken to reach equilibrium depends on the difference in WHC values between the previous and current food and that the capacity to consume food bulk is related to the WHC of the current food. It is proposed that the capacity for WHC on the first day on a new food will be equal to the current capacity for WHC on the last day of the previous food. Thus where FI is food intake (kg/d). Thereafter Cwhc will gradually increase over time to a maximum of 0.27 g/kg. The rate of change in Cwhc is made to be the same for all pigs and all foods. The increase in capacity over time is assumed to be linear at the rate of 0.01 units/d. The model was tested using published data. Qualitatively the predictions of the model were in close agreement with the relevant observed data in at least some cases. It is concluded that the underlying theoretical assumptions of the model are reasonable. However, the model fails to predict initial intake when changed to foods high in wheat-bran content and fails to predict the intake of a non-limiting food where compensatory increases in intake and gain occur. The model could be adapted to overcome the first failure by taking into account the time course of digestive efficiency following a change in food. To deal with the second would require a sufficient understanding of the time course of compensatory growth.     

Hypercalcaemia in Greek patients with tuberculosis before the initiation of anti-tuberculosis treatment

Hypercalcaemia has been known to occur in association with granulomatous diseases. The aim of this study was to ascertain the incidence of hypercalcaemia and determine the prevalence of symptoms associated with it in Greek patients with newly-diagnosed tuberculosis (TB), before the initiation of anti-tuberculosis treatment. We prospectively evaluated all patients with newly-diagnosed TB presenting, either as inpatients or as outpatients, to our hospital, during a 3-year period. We evaluated 88 patients with TB (50 males and 38 females), aged between 23 and 89 years (mean age+/-SD: 46.4+/-19 years), and 65 age- and sex-matched controls with chronic obstructive pulmonary disease (36 males and 29 females), aged between 28 and 88 years (mean age+/-SD: 47.2+/-18 years). Among TB patients, 56 had pulmonary TB, 20 had pleural TB without evidence of pulmonary parenchyma involvement, eight had pulmonary and pleural TB, and four had disseminated disease. The mean (+/-SD) albumin-adjusted serum calcium concentration and the mean ionized calcium concentration were significantly higher in the TB group (2.49+/-0.21 mmol l(-1) and 1.27+/-0.02 mmol l(-1) respectively) than in the control group (2.36+/-0.11 mmol l(-1) and 1.19+/-0.02 mmol l(-1), P<0.05). In the TB group no correlation between type of disease and albumin-adjusted or ionized calcium concentration was seen. Hypercalcaemia was detected in 22 patients with TB (25%) but only three showed symptoms associated with it. We conclude that, although hypercalcaemia is a common laboratory finding among Greek patients with TB before anti-TB chemotherapy, it is usually asymtomatic.