Analysis of the histologic features in the differential diagnosis of intrahepatic neonatal cholestasis

AIM： To compare the histologic features of the liver in intrahepatic neonatal cholestasis （IHNC） with infectious, genetic-endocrine-metabolic, and idiopathic etiologies. METHODS： Liver biopsies from 86 infants with IHNC were evaluated. The inclusion criteria consisted of jaundice beginning at 3 mo of age and a hepatic biop- sy during the 1st year of life. The following histologic features were evaluated： cholestasis, eosinophilia, giant cells, erythropoiesis, siderosis, portal fibrosis, and the presence of a septum. RESULTS： Based on the diagnosis, patients were classified into three groups： group 1 （infectious; n = 18）, group 2 （genetic-endocrine-metabolic; n = 18）, and group 3 （idiopathic; n = 50）. There were no significant differences with respect to the following variables： cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and presence of a septum. A significant dif- ference was observed with respect to erythropoiesis, which was more severe in group 1 （Fisher＇s exact test, P = 0.016）. CONCLUSION： A significant difference was observed in IHNC of infectious etiology, in which erythropoiesis was more severe than that in genetic-endocrine-meta- bolic and idiopathic etiologies, whereas there were no significant differences among cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and the presence of a septum.     

Intubation for patients with overdose: Time to move on from the Glasgow Coma Scale

Patients frequently present to the ED with drug overdose and reduced conscious level leading to coma. There is considerable practice variation around which patients require intubation. Indications include: (i) respiratory failure (including airway obstruction); (ii) to facilitate specific therapies or intubation as a therapy in itself; and (iii) for airway protection in the unprotected airway. We argue that intubating a patient purely for (iii) is outdated and that most patients can be safely observed. There is a paucity of good quality research in the area of drug overdose with reduced consciousness. Teaching may be outdated and based on the use of the Glasgow Coma Scale in head trauma. Current low quality research suggests observation is safe. We recommend that patients undergo an individualised risk assessment of the need for intubation. We propose a flow diagram to aid clinicians in safely observing comatose overdose patients. This can be applied if the drug is unknown, or there are multiple drugs involved.     

Is an isolated fetal cardiac echogenic focus an indication for fetal echocardiography?

OBJECTIVE: To determine whether the presence of an isolated fetal cardiac echogenic focus should be an indication for fetal echocardiography. METHODS: We reviewed our fetal echocardiography and obstetrics databases from January 1992 through July 1999. The study groups were formulated from patients referred for fetal echocardiography. Patients referred for echocardiography because of a single isolated fetal cardiac echogenic focus were compared with patients referred for other indications. The sensitivity, specificity, and positive and negative predictive values were calculated for an isolated echogenic focus as a marker for structural cardiac abnormalities as detected by fetal echocardiography. RESULTS: Of 10,406 fetuses seen for ultrasonography, 1908 had fetal echocardiography. Cardiac abnormalities were identified in 3.4% (65 of 1908) of the fetuses that had echocardiography. The prevalence of an isolated echogenic focus was 2.2% (230 of 10,406) and was the indication in 12.1% (230 of 1908) of our echocardiograms. Only 1 of the 230 fetuses with an isolated echogenic focus had a structural cardiac defect (membranous ventricular septal defect). An isolated echogenic focus as a marker for congenital cardiac defects resulted in sensitivity and specificity of 1.5% and 87.6%, respectively. The positive and negative predictive values were 0.4% and 96.2%, respectively The relative risk for an echogenic focus in predicting congenital cardiac defects was 0.11 (95% confidence interval, 0.02-0.82). CONDUSIONS: An isolated fetal cardiac echogenic focus is not an efficacious marker for congenital cardiac defects. It should not be the sole indication for fetal echocardiography.     

The cost of hospital-related care of patients with psoriasis in Italy based on the AISP study

The objective of this study was to assess the cost of caring for patients with psoriasis in Italy according to the AISP study (Associazione Italiana Studi Psoriasi or Italian Association for Studies on Psoriasis), involving 104 university and hospital centres and 7992 patients in 1994. The mean yearly cost of care for a single patient was calculated at 905 Euros. Hospitalization accounted for more than four-fifths of the costs, therapy for about one-eighth (systemic therapies were the most expensive) and office visits and day hospitals for the remainder. In our study series less than 20% of patients accounted for more than 90% of the total costs.     

WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma [published erratum appears in Hum Mol Genet 1998 Sep;7(9):1527]

Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3). The smallest region of overlap between WHS patients, the WHS critical region, has been confined to 165 kb, of which the complete sequence is known. We have identified and studied a 90 kb gene, designated as WHSC1 , mapping to the 165 kb WHS critical region. This 25 exon gene is expressed ubiquitously in early development and undergoes complex alternative splicing and differential polyadenylation. It encodes a 136 kDa protein containing four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain also found in the Drosophila dysmorphy gene ash -encoded protein, and a PHD-type zinc finger. It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients. The nature of the protein motifs, the expression pattern and its mapping to the critical region led us to propose WHSC1 as a good candidate gene to be responsible for many of the phenotypic features of WHS. Finally, as a serendipitous finding, of the t(4;14) (p16.3;q32.3) translocations recently described in multiple myelomas, at least three breakpoints merge the IgH and WHSC1 genes, potentially causing fusion proteins replacing WHSC1 exons 1-4 by the IgH 5'-VDJ moiety.      

Abrogation of Microsatellite-instable Tumors Using a Highly Selective Suicide Gene/Prodrug Combination

A substantial fraction of sporadic and inherited colorectal and endometrial cancers in humans is deficient in DNA mismatch repair (MMR). These cancers are characterized by length alterations in ubiquitous simple sequence repeats, a phenotype called microsatellite instability. Here we have exploited this phenotype by developing a novel approach for the highly selective gene therapy of MMR-deficient tumors. To achieve this selectivity, we mutated the VP22FCU1 suicide gene by inserting an out-of-frame microsatellite within its coding region. We show that in a significant fraction of microsatellite-instable (MSI) cells carrying the mutated suicide gene, full-length protein becomes expressed within a few cell doublings, presumably resulting from a reverting frameshift within the inserted microsatellite. Treatment of these cells with the innocuous prodrug 5-fluorocytosine (5-FC) induces strong cytotoxicity and we demonstrate that this owes to multiple bystander effects conferred by the suicide gene/prodrug combination. In a mouse model, MMR-deficient tumors that contained the out-of-frame VP22FCU1 gene displayed strong remission after treatment with 5-FC, without any obvious adverse systemic effects to the mouse. By virtue of its high selectivity and potency, this conditional enzyme/prodrug combination may hold promise for the treatment or prevention of MMR-deficient cancer in humans.