[The use of RCGO triggers in the obstetric - gynecological procedures: the impact on the reduction of adeverse events. The experience of the Lombardia Region]. / L'utilizzo dei RCOG trigger in area ostetrica - ginecologica e la riduzione degli eventi avversi. L'esperienza della regione Lombardia.

The last few weeks of pregnancy are critical to a baby's health because important organs, including the brain and lungs, are not completely developed until the end of pregnancy. The adverse events during labor and childbirth can have very serious physical, psychological and financial consequences for the child, the family, health professionals and the whole community. These events can be reduced through interventions aimed at improving the safety and quality of care, based on evidence-based knowledge, guidelines and practices that must be widely and effectively applied. This work reports the experience of the Lombardy Region on improvement actions in the obstetric and gynecological procedures for the reduction of adverse events and sentinel events through the monitoring and management of the RCGS trigger tool.

Are ultrasonographic myoma characteristics associated with blood loss at delivery?

OBJECTIVES: The presence of myomas in pregnancy is associated with greater blood loss at delivery. The aim of this study was to evaluate whether the sonographic characteristics of myomas can predict blood loss at delivery in women with large myomas. METHODS: Among women who underwent second-trimester ultrasound screening at our department between January 1996 and December 2004, 251 had at least one myoma with a mean diameter > or = 5 cm. Number of myomas (single vs. multiple), maximum diameter of the largest myoma, sum of the maximum diameter of each myoma, change in size of myomas between first and last scan, and location in relation to the placenta and to the presenting part of the fetus (above or below) were analyzed in relation to blood loss at delivery and severe postpartum hemorrhage (> or = 1000 mL). RESULTS: Multivariate analysis showed that the presence of multiple myomas was the only parameter independently associated with amount of blood loss at delivery (P = 0.003). The association between the presence of multiple myomas and severe postpartum hemorrhage was of borderline significance for the statistical power of this study (P = 0.08). CONCLUSIONS: In women with large myomas, the presence of multiple tumors is independently associated with heavier blood loss at delivery but not with postpartum hemorrhage of > or = 1000 mL.

Amnioinfusion in preterm PROM: effects on amnion and cord histology.

OBJECTIVE: To investigate the effects of transabdominal amnioinfusion (TA) on the histology of amnion (A) and umbilical cord (UC). STUDY DESIGN: From a cohort of 56 singleton pregnancies with premature rupture of membranes (PROM) at

Control of the CFTR channel's gates.

Unique among ABC (ATP-binding cassette) protein family members, CFTR (cystic fibrosis transmembrane conductance regulator), also termed ABCC7, encoded by the gene mutated in cystic fibrosis patients, functions as an ion channel. Opening and closing of its anion-selective pore are linked to ATP binding and hydrolysis at CFTR's two NBDs (nucleotide-binding domains), NBD1 and NBD2. Isolated NBDs of prokaryotic ABC proteins form homodimers upon binding ATP, but separate after hydrolysis of the ATP. By combining mutagenesis with single-channel recording and nucleotide photolabelling on intact CFTR molecules, we relate opening and closing of the channel gates to ATP-mediated events in the NBDs. In particular, we demonstrate that two CFTR residues, predicted to lie on opposite sides of its anticipated NBD1-NBD2 heterodimer interface, are energetically coupled when the channels open but are independent of each other in closed channels. This directly links ATP-driven tight dimerization of CFTR's cytoplasmic NBDs to opening of the ion channel in the transmembrane domains. Evolutionary conservation of the energetically coupled residues in a manner that preserves their ability to form a hydrogen bond argues that this molecular mechanism, involving dynamic restructuring of the NBD dimer interface, is shared by all members of the ABC protein superfamily.

Isolated fetal choroid plexus cysts: role of ultrasonography in establishment of the risk of trisomy 18.

OBJECTIVE: The significance of isolated choroid plexus cysts found by ultrasonographic scan during the second trimester as a marker for trisomy 18 is still debated. We analyzed our data and reviewed the series published in the English-language literature to calculate the likelihood ratio of trisomy 18 in the presence of isolated choroid plexus cysts; that is, the factor by which the individual risk of trisomy 18 is increased in the presence of isolated choroid plexus cysts. STUDY DESIGN: Likelihood ratios were calculated as ratio of the sensitivity to the false-positive rate. Sensitivity was defined as the rate of isolated choroid plexus cysts detected at midgestation among fetuses with trisomy 18. False-positive rate was defined as the rate of choroid plexus cysts detected at midgestation in the population without trisomy 18. The sensitivities of all published series reporting rates of choroid plexus cysts at the time of the first ultrasonographic examination between 14 and 24 weeks' gestation in populations with trisomy 18 and in low-risk populations were included in the analysis. To these we added all cases of trisomy 18 diagnosed at our institution during the period January 1, 1988, through June 30, 1998, in which prenatal ultrasonographic examination was performed between 14 and 24 weeks' gestation. RESULTS: The prevalence of second-trimester ultrasonographic detection of isolated choroid plexus cysts among fetuses with trisomy 18 was 6.7% (13/194), whereas that in the population without trisomy 18 was 0.9% (752/79,583). The likelihood ratio associated with isolated choroid plexus cysts was therefore 7.09 (95% confidence interval, 3.97-12.18). CONCLUSION: The presence of isolated second-trimester choroid plexus cysts increases the base risk of trisomy 18 by a factor of 7.09. This likelihood ratio can be multiplied by the risk calculated according to maternal age to obtain the individual risk of trisomy 18 and thus permit more accurate counseling of the patient.

Alterations in the retinoblastoma pathway of cell cycle control in parathyroid tumors.

Mutations in proto-oncogenes and tumor suppressor genes have been associated with tumor development and/or progression in many neoplasms. It has been reported that parathyroid tumors have deletions affecting the retinoblastoma gene (RB), and overexpression of cyclin D1 (Cyc D1). The aim of the present study was to evaluate the alterations in the components of the pRB pathway in parathyroid adenomas and parathyroid aggressive tumors, including patterns of expression of pRB, Cyc D1, and p16/INK4A. Paired normal and tumor DNA from 6 parathyroid adenomas and 5 aggressive tumors were analyzed for loss of heterozygosity (LOH) at the RB locus. The expression of pRB, Cyc D1 and p16 was studied in 4 adenomas and 5 aggressive tumors. RB LOH was found in 1 of 6 adenomas, and in 1 of 2 informative aggressive tumors. Immunohistochemical analysis revealed undetectable pRB in 4 of 5 aggressive tumors and presence of pRB in all adenomas. Conversely, Cyc D1 expression was found in 3 of 4 aggressive tumors, but was undetectable in the adenomas. Expression of p16 was identified only in one aggressive tumor. Thus, alterations in the pRB pathway seem to prevail in the aggressive form of parathyroid neoplasms. Our results warrant further investigation of these cell cycle regulators in order to determine their potential role as tumor markers in parathyroid tumors.

Critical appraisal of the use of nuchal fold thickness measurements for the prediction of Down syndrome.

OBJECTIVE: Nuchal fold thickness is the best ultrasonographic predictor of fetal trisomy 21. However, the risk assigned on the basis of the commonly used threshold of nuchal fold thickness >/=6 mm does not take into consideration the significant associations between nuchal fold thickness and gestational age and between maternal age and Down syndrome. We propose a new method of calculating Down syndrome probability that takes into account both gestational age at examination and previously assessed probability of Down syndrome. STUDY DESIGN: Nuchal fold thickness was measured at ultrasonographic examination at 14 to 22 weeks' gestation without previous knowledge of the fetal karyotype. Nuchal cystic hygromas were excluded from analysis. Statistical analyses included correlation, logistic regression to control for other ultrasonographic predictors of trisomy 21 and for maternal age, receiver operating characteristic curve, and likelihood ratios (defined as the ratio of the sensitivity to the false-positive rate). P <.05 was considered significant. RESULTS: Mean gestational age at ultrasonography was 16.9 weeks' gestation (range, 14-22 weeks' gestation). Mean (+/-SD) nuchal fold thickness in fetuses with trisomy 21 (4.7 +/- 1.6 mm; n = 29) was greater than in euploid fetuses (3.2 +/- 0.9; n = 780; P <.001). Logistic regression analysis established that nuchal fold thickness was a significant predictor of trisomy 21 independent both of the other ultrasonographic markers and of maternal age (P <.001). Regression analysis showed that nuchal fold thickness was significantly correlated with gestational age among both fetuses with trisomy 21 and euploid fetuses and that the regression line of fetuses with trisomy 21 had a slope similar to that of euploid fetuses. The difference between observed and expected nuchal fold thicknesses on the basis of the biparietal diameter (as a function of gestational age) was used to obviate the confounding effect of gestational age. Differences between observed and expected nuchal fold thicknesses were then used to calculate likelihood ratios. These likelihood ratios could then be multiplied by the individual prior probability to obtain a patient-specific Down syndrome probability. CONCLUSION: Nuchal fold thickness is correlated with gestational age in both euploid fetuses and fetuses with Down syndrome. Use of the difference between observed and expected nuchal fold thicknesses to determine likelihood ratios allows the calculation of individual posterior probabilities of Down syndrome that take into consideration both gestational age and maternal age.

Best second trimester sonographic markers for the detection of trisomy 21.

We analyzed all genetic sonograms obtained during a 6 year period to establish the independent ability of the following sonographic markers of aneuploidy in the diagnosis of trisomy 21: structural anomalies, cardiac abnormalities, nuchal fold thickness of 6 mm or greater, bowel echogenicity, choroid plexus cysts, and renal pyelectasis. With the exception of bowel echogenicity and choroid plexus cysts, the sonographic markers were more common in trisomy 21 than euploid fetuses (all P < 0.001). Logistic regression analysis demonstrated that cardiac anomalies (odds ratio = 255; 95% confidence interval, 25, 2592), other structural anomalies (odds ratio = 25; 95% confidence interval, 6, 97), and nuchal fold thickness of 6 mm or greater (odds ratio = 13; 95% confidence interval, 3, 50) were the only independent predictors of trisomy 21. The false-positive rate and sensitivity were 5.3% (48 of 898) and 59.2% (13 of 22), respectively, when any of the sonographic markers significant at univariate analysis was considered, and 3.1% (28 of 898) and 54.5% (12 of 22), respectively, when any of the predictors at multivariate analysis was present. Because a considerable overlap of sonographic markers exists among trisomy 21 fetuses, use of those that are not independent predictors leads to an increase in false-positive rate without a gain in sensitivity.

Ultrasonographic differential diagnosis of fetal intracranial interhemispheric cysts.

OBJECTIVE: Ultrasonographic differentiation between intracranial supratentorial interhemispheric pathologic cystlike lesions and those related to physiologic median structures is essential because the latter have no clinical relevance, whereas the former may carry a poor prognosis. We reviewed our experience with 19 consecutive cases of interhemispheric hypoechoic lesions without parenchymal involvement diagnosed between January 1990 and June 1997 to establish their clinical significance and provide prenatal ultrasonographic criteria to distinguish between pathologic cystlike lesions and those related to physiologic midline structures. STUDY DESIGN: All patients underwent targeted prenatal scans of intracranial anatomy to establish the relationship between the fluid collections and the surrounding parenchymal and ventricular structures. In addition, a detailed anatomic survey was performed to rule out associated malformations. Follow-up, including neurologic examination, imaging, autopsy evaluation, or a combination was performed in all cases. Statistical analysis used the Wilcoxon rank sum test, the Fisher exact test, and the chi2 test for trend. P <.05 was considered significant. RESULTS: Cystlike lesions related to physiologic median structures (n = 12) included enlargement of the cavum septi pellucidi (n = 3), enlargement of the cavum vergae (n = 2), and cysts of the velum interpositum (n = 7). These lesions were unilocular and had a median size of 10 mm (range 10-30 mm); they resolved in 5 cases and remained stable in the remainder. They were not associated with overt abnormalities, other than borderline ventriculomegaly in 2 cases. Pediatric follow-up (median 26 months, range 3-84 months) showed normal neurodevelopment in all cases. Pathologic cystlike lesions (n = 7) were significantly larger (median 40 mm, range 10-80 mm, P =.004) and had a significantly worsening trend, growing more at serial prenatal ultrasonographic examinations (P =.039) than fluid collections related to physiologic median structures. Moreover, prenatal ultrasonographic evidence of associated intracranial abnormalities, in the form of partial or total agenesis of the corpus callosum and overt hydrocephalus, was present in 5 of 7 cases of pathologic cystlike lesions and in none of the 12 related to physiologic structures (P =.002). Median gestational age at diagnosis was not different between those with cystlike lesions related to physiologic median structures and those with pathologic lesions (30 and 31 weeks, respectively). Among the latter group, 1 pregnancy was voluntarily terminated, 1 infant died at 4 months of age, 2 infants had neurodevelopmental delay, and 3 infants were neurologically healthy at a mean follow-up of 43 months. Cyst shunting was necessary in 5 of 6 cases. CONCLUSIONS: Interhemispheric cystlike lesions related to physiologic structures can be prenatally distinguished from pathologic fluid collections on the basis of location, cyst size, change in size with time, and absence of associated anomalies.

[Identification of Epstein-Barr virus in nasopharyngeal carcinomas in Argentina. Its relation with p53 and the determination of proliferation indices]. / Identificación del virus Epstein-Barr en carcinomas nasofaríngeos en Argentina. Su relación con p53 y determinación de índices de proliferación.

Thirty-seven nasopharyngeal carcinomas were studied obtaining the tissue from nasopharyngeal biopsies that were formalin fixed and paraffin embedded. The patients were born in Argentina, 23 men and 14 women with a mean age of 50 years. Histologically the tumors were classified as queratinizing squamous cell carcinomas, 1 case (2%); non-queratinizing squamous cell carcinomas, 15 cases (41%) and undifferentiated carcinomas, 21 cases (57%). The proliferating index (PI) was determined using monoclonal antibodies against PCNA and Ki-67 (MIB-1), resulting in 26% for PCNA and 17% for Ki-67 while no differences were found comparing PI with histological type and cases with clinical stage III and IV. The PI was of 2% in the 3 cases with clinical stage II. Immunostains for p53 were positive in 30 out of the 37 cases with no differences between the histological types, exception made for the queratinizing carcinoma which was negative. With a cut off point of 7% in the 12 cases with follow up, two groups were found with a mean survival of 35 and 12 months, a finding that was not statistically significant. Epstein-Barr virus was detected by PCR using the paraffin embedded material in 31 out of the 37 cases: 21 were undifferentiated carcinomas and 15 non-queratinizing squamous cell carcinomas; the queratinizing squamous cell carcinoma was negative. These results, published for the first time in samples from Argentinian patients are similar to those found in areas of high and low incidence of nasopharyngeal carcinomas and can be of clinical use in determining the nasopharyngeal origin of a cervical metastatic lymph node of an unknown primary.

Intrauterine diagnosis and management of transient myeloproliferative disorder.

Transient myeloproliferative disorders can be associated with hydrops in Down syndrome fetuses. No cases of prenatal management of such a condition have been reported in the literature. We report a case of myeloproliferative disorder diagnosed by cordocentesis at 31 weeks in a Down syndrome fetus with pericardial effusion. A pericardiocentesis was performed at the first signs of hydrops and successfully improved fetal cardiac function, allowing for continuation of pregnancy.

Do uterine leiomyomas influence pregnancy outcome?

To evaluate the clinical significance of the presence, location, size, and number of uterine leiomyomas in pregnancy, a retrospective cohort study in which pregnancy complications and outcome of pregnant women with uterine myomas was undertaken by routine second trimester ultrasound examination. The case group consisted of 183 consecutive women with uterine myomas detected and followed during the years 1983-1989; the control group was made up of all pregnancies diagnosed and followed at the obstetric clinic during the period 1985-1987. The incidences of preterm delivery (less than 37 weeks), preterm premature rupture of membranes, in utero growth retardation (less than 5th percentile), placental abruptio, placenta previa, postpartum hemorrhage (more than 500 cc), and retained placenta were not significantly increased in the group of women with myomas compared with the general population. However, cesarean sections were more common in women with myomas (23 vs 12%; P < 0.001). Within the group of women with myomas, the incidence of cesarean section was not different in cases with multiple rather than solitary myomas, but it was significantly higher in cases of lower uterine segment compared with fundal myomas (39 vs 18%; P < 0.01) and when the mean diameter of the myoma was greater than 5 cm (35 vs 17%; P = 0.01). Stepwise logistic regression analysis showed that both myoma location and size were independent predictors of the odds of cesarean section.

Color Doppler ultrasound in the preoperative assessment of adnexal masses.

OBJECTIVE: To differentiate benign from malignant ovarian tumors preoperatively by means of transvaginal color Doppler ultrasound and to compare the sensitivity and specificity of this technique with that of conventional transvaginal ultrasound and CA 125 serum levels. METHODS: Different indicators of blood flow resistance (pulsatility index and resistance index) within intratumoral vessels were evaluated preoperatively in 80 adnexal masses by means of color Doppler ultrasound. Results were compared to CA 125 levels, conventional ultrasound and histopathologic findings. RESULTS: Forty-seven benign, 29 malignant and four borderline masses were studied. Mean PI and RI were significantly higher in benign than in malignant masses but an overlap was observed. Sensitivity, specificity and accuracy of color Doppler in predicting malignancy were 85%, 91% and 89% by using a cut-off value of 0.56 for resistance index and 97%, 87%, 91% by using a cut-off value of 1.0 for pulsatility index. The accuracy of both indexes in differentiating benign from malignant tumors was superior to that obtained by using conventional ultrasound and CA 125. In eight of nine masses where disagreement existed between color Doppler ultrasound and conventional ultrasound, pathologic examination confirmed the nature suggested by color Doppler ultrasound. CONCLUSIONS: Compared to conventional ultrasound and CA 125, color Doppler ultrasound was more accurate in discriminating malignancies from benign tumors. The best use for this technique seems in giving further preoperative information about masses with uncertain sonographic characteristics, allowing better timing and tailoring of surgery.

Natural history of uterine leiomyomas in pregnancy.

A prospective study was conducted over a 6 year period to determine the natural history of uterine leiomyomas in pregnancy. All pregnant women with myomas detected during obstetric ultrasonographic examination and with three or more sonographic examinations were included; 134 patients fulfilled the inclusion criteria. Sonograms were obtained at 2 week intervals until 20 weeks of gestation, and monthly thereafter. The following observations were made: (1) the majority of myomas 5 cm or less in average diameter could no longer be seen during pregnancy; (2) the majority of myomas greater than 5 cm in diameter tended to remain stable or decrease in size during pregnancy; and (3) multiple myomas were less likely to disappear than solitary myomas.

Expression of IL-6 mRNA in normal rat and human pituitaries and in human pituitary adenomas.

Cells expressing IL-6 mRNA were detected by in situ hybridization in normal pituitaries. In normal untreated rat pituitary the expression was very low. Within hours after IP administration of liposaccharide, IL-6 mRNA accumulated in the anterior lobe of the pituitary. Production of IL-6 was monitored after dissociation and culture of pituitary cells. High levels (8000 pg/ml) were recovered after 72 hr in culture. In normal human pituitaries, less than 1% of cells expressed IL-6 mRNA or IL-6 receptor mRNA (IL-6-R mRNA). In gonadotropinomas, prolactinomas, and non-functioning adenomas, only rare, scattered positive cells were found for either IL-6 or IL-6-R. In contrast, both genes were highly expressed in ACTH- and GH-secreting tumors at the junction of adenoma and infiltrating fibrous tissue and around blood vessels. The combined expression of IL-6 and IL-6-R suggests that IL-6 acts in an autocrine or in a paracrine way in ACTH and GH adenomas.

Receptors for pituitary adenylate cyclase activating peptides in human pituitary adenomas.

The presence of pituitary adenylate cyclase activating polypeptide (PACAP) receptors coupled to adenylate cyclase was investigated in four types of human pituitary adenomas: three null adenomas and five gonadotropin-, three ACTH-, four GH-, and four PRL-producing adenomas. In all samples, except in prolactinomas, PACAP(1-27) and PACAP(1-38) stimulated adenylate cyclase activity equally well and potently (K(act) around 3 nmol). Vasoactive intestinal polypeptide (VIP) was systematically 100- to 300-fold less potent than both PACAPs. In prolactinomas, PACAP(1-27), PACAP(1-38), and VIP were inactive despite a response of the enzyme to guanosine 5'-triphosphate, Gpp(NH)p, forskolin, and fluoride. [125I-AcHis1]PACAP(1-27) binding was detected in all samples except in prolactinomas. In addition, a detailed analysis of receptors was feasible in all five gonadotropin- and in two ACTH-producing adenomas, confirming the existence of selective PACAP receptors that recognized PACAP(1-27) and PACAP(1-38) with similar high affinity (IC50 0.8-1.5 nmol) and VIP with a low affinity (IC50 100 nmol/L).

Pit-1/GHF-1 expression in pituitary adenomas: further analogy between human adenomas and rat SMtTW tumours.

Adenomas can develop from each cell type of the anterior pituitary. In the normal pituitary, three of these cells types, the GH-, prolactin- and TSH-secreting cells, express the transcription factor Pit-1/GHF-1 which is responsible for prolactin and GH (and probably TSH) cell commitment, differentiation, probably proliferation and gene expression. We have analysed the expression of Pit-1/GHF-1 in a panel of human pituitary adenomas. All GH-, prolactin- and TSH-expressing adenomas studied expressed the Pit-1/GHF-1 factor, as demonstrated by in-situ hybridization and immunocytochemistry. The expression was higher in adenomas than in normal human pituitary. In contrast, ACTH- and LH-FSH-secreting and non-secreting adenomas were negative. Seven transplants of the spontaneous rat prolactinoma SMtTW were also investigated and all were found to be positive. This further stresses the analogy between these tumours and human prolactinomas. Taken together, the data confirm that Pit-1/GHF-1 expression is restricted to GH-, prolactin- and TSH-expressing cells, and the increased expression in adenomas is compatible with a role of Pit-1/GHF-1 in cell proliferation.

Growth hormone and prolactin are paracrine growth and differentiation factors in the haemopoietic system.

The pituitary secretory proteins growth hormone (GH) and prolactin (PRL) do not, as yet, have major roles in haematology or immunology. Recent evidence indicates that these hormones are haemopoietic growth factors and exert immunomodulatory functions at physiological concentrations. Here Robert Hooghe and colleagues discuss the significance of these hormones on different aspects of the immune system.

The transcription factor Pit-1/GHF-1 is expressed in hemopoietic and lymphoid tissues.

The expression of the Pit-1/GHF-1 transcription factor (hereafter Pit-1), which controls the expression of growth hormone (GH) and prolactin (PRL) in the pituitary gland, has been documented in human and rat hemopoietic and lymphoid tissues and cell lines. Pit-1 mRNA was detected by in situ hybridization in about 1% of rat bone marrow cells and in the spleen red pulp and marginal zone. Pit-1 was also expressed in human tonsils (mantle zone), in the thymus (rat and human, non-lymphoid cells), in lipopolysaccharide-stimulated rat peritoneal cells and in non-hepatocyte cells in the liver (rat and human). A detailed investigation of the rat spleen showed a very similar distribution for Pit-1, GH and PRL mRNA and Pit-1, GH and PRL proteins (detected by immunocytochemistry). Using polymerase chain reaction followed by Southern hybridization, the expression of Pit-1 could be confirmed in human and rat spleen, bone marrow and thymus. HL60 and RAJI leukemic cells were also positive. The sequence of fragments amplified from rat spleen and from human bone marrow completely matched published sequences of rat and human pituitary Pit-1, respectively. Expression of GH and PRL in lymphoid tissues has been documented. The straightforward hypothesis would therefore be that Pit-1's main function in lymphoid tissues is controlling GH and PRL expression, as in the pituitary gland. GH and PRL may be hemopoietic and lymphoid growth and differentiation factors.

Results of a preventive program for congenital toxoplasmosis.

All pregnant women followed during the period 1982-87 were screened for toxoplasmosis, and 35 patients had documented seroconversion or doubtful toxoplasmosis titers. One patient opted for pregnancy termination. The remaining were followed with a protocol that included serial ultrasound examinations and prophylactic antibiotic treatment of the mother and neonate. No fetal abnormalities related to congenital toxoplasmosis were found. All the infants had negative toxoplasmosis test titers at birth; at follow-up only one was found to have developed a subclinical infection, at 2 months of age. Our data suggest that antiparasitic treatment during pregnancy for those at risk for Toxoplasma infection may reduce the transmission rate.