Induced luteolysis in the primate: rapid loss of luteinizing hormone receptors

The molecular mechanisms involved in luteolysis are still unclear in the primate. This study aimed to investigate the effect of induced luteolysis on the ovarian luteinizing hormone (LH) receptor and the steroidogenic enzyme, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the marmoset monkey. Luteolysis was induced in the mid-luteal phase either directly by systemic prostaglandin F2alpha (PGF2alpha), or indirectly by LH withdrawal using systemic gonadotrophin releasing hormone antagonist (GnRHant) treatment. The LH receptor was studied by isotopic mRNA in-situ hybridization and in-situ ligand binding and 3beta-HSD expression was studied using isotopic mRNA in-situ hybridization and immunohistochemistry. Induced luteolysis was associated with a reduction in the expression of LH receptor (P < 0.0001) and 3beta-HSD mRNA, closely followed by a reduction in the LH receptor (P < 0.05) and 3beta-HSD protein concentrations within 24 h. There were no differences in the findings whether luteolysis was induced with PGF2alpha or GnRHant. This study shows that disparate mechanisms to induce luteolysis in the primate result in an identical rapid loss of the LH receptor and 3beta-HSD. In conclusion, induced luteolysis leads to rapid loss of the steroidogenic pathway in luteal cells.      

X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase

X-linked liver glycogenosis type II (XLG II) is a recently described X- linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.      

Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques

Our purpose in this study was to evaluate the variability of manual mesothelioma tumor thickness measurements in computed tomography (CT) scans and to assess the relative performance of six computerized measurement algorithms. The CT scans of 22 patients with malignant pleural mesothelioma were collected. In each scan, an initial observer identified up to three sites in each of three CT sections at which tumor thickness measurements were to be made. At each site, five observers manually measured tumor thickness through a computer interface. Three observers repeated these measurements during three separate sessions. Inter- and intra-observer variability in the manual measurement of tumor thickness was assessed. Six automated measurement algorithms were developed based on the geometric relationship between a specified measurement site and the automatically extracted lung regions. Computer-generated measurements were compared with manual measurements. The tumor thickness measurements of different observers were highly correlated (r > or = 0.99); however, the 95% limits of agreement for relative inter-observer difference spanned a range of 30%. Tumor thickness measurements generated by the computer algorithms also correlated highly with the average of observer measurements (r > or = 0.93). We have developed computerized techniques for the measurement of mesothelioma tumor thickness in CT scans. These techniques achieved varying levels of agreement with measurements made by human observers.     

Prophylaxis in RSV infection (Palivizumab)--is it worthwhile?

Respiratory syncytial virus (RSV) is a recognised cause of lower respiratory tract infection in infants and young children. It causes severe respiratory disease in preterm infants with or without chronic lung disease. This study, conducted at Waterford Regional Hospital, evaluates the incidence of RSV infection in hospitalised children, its seasonal variation, and effectiveness of its prevention. Thirty eight percent of admitted children with bronchiolitis were RSV positive in the year 1999 November to March is the peak season for this infection. A highly selected group of 7 preterm children with or without chronic lung disease received Palivizumab prophylaxis. Not one of them acquired RSV infection. The high cost of Palivizumab was the main factor for its restricted use. Palivizumab was found to be effective in preventing RSV infection in our study. Since we had a small number of patients, further studies are needed for its economic and judicious use. Respiratory syncytial virus (RSV) is virulent easily transmissible and the most common cause of lower respiratory tract disease in children of less than 2 years of age. Up to 98% of children attending day care will be infected in single RSV season. Between 0.5% and 3.2% of children with RSV infection require Hospitalisation. Approximately 90,000 hospital admissions and 4500 deaths per year were reported in United States. In Ireland 2807 patients were admitted with Bronchiolitis in 1998. Major risk factors for hospitalisation due to RSV are Prematurity, chronic lung disease, congenital heart disease, compromised immunity and age younger then 6 weeks in otherwise healthy children. No effective treatment of RSV positive bronchiolitis beside supportive care in the form of adequate nutrition and oxygen therapy is available. Antiviral therapies such as Ribavirin has not been proved to be effective in RSV infection. Bronchodilators show variable results. Corticosteroids were not found effective. There is no effective vaccine available as yet. There is no proven method for active immunity. Various immunoglobulins are available for acquiring passive immunity against RSV infection. PREVENT study group in Jan. 1997 showed intravenous immunoglobulin (RSV- IGIV) use in reducing 41% to 63% hospitalisation in RSV patients. But RSV-IGIV was not licensed outside the United States because of risk of transmission of blood borne products, difficulty in administration ie. intravenous access, large fluid volume (15 ml/kg), high protein load (750 mg/kg), shortage of supply and need to postpone live vaccine (eg. MMR, varicella). monoclonal antibody Palivizumab was developed for prophylaxis against RSV infection. Clinical safety and efficacy of Palivizumab were demonstrated in IMpact trial published in Sept. 1998. Reduction in hospitalisation up to 55% was noted in this study. It was a pivotal randomised, double blind, placebo controlled phase 3 study conducted in 139 centres throughout Canada, United States and United Kingdom. We looked at our experience in patients admitted with bronchiolitis in Waterford Regional Hospital. We described the outcome of carefully selected Seven children of high risk group for Palivizumab prophylaxis. Its clinical Implications and cost effectiveness was evaluated in this study.     

L1 knockout mice show dilated ventricles, vermis hypoplasia and impaired exploration patterns

L1 is a neural cell adhesion molecule mainly involved in axon guidance and neuronal migration during brain development. Mutations in the human L1 gene give rise to a complex clinical picture, with mental retardation, neurologic abnormalities and a variable degree of hydrocephalus. Recently, a transgenic mouse model with a targeted null mutation in the L1 gene was generated. These knockout (KO) mice show hypoplasia of the corticospinal tract. Here we have performed further studies of these KO mice including magnetic resonance imaging of the brain, neuropathological analysis and behavioral testing. The ventricular system was shown to be abnormal with dilatation of the lateral ventricles and the 4th ventricle, and an altered shape of the Sylvius aqueduct. Additionally, the cerebellar vermis of the KO mice is hypoplastic. Their exploratory behavior is characterized by stereotype peripheral circling reminiscent of that of rodents with induced cerebellar lesions.      

Three novel PROC gene lesions causing protein C deficiency

Hallam PJ, Mannucci P, Tripodi A, Bevan D, Laursen B, Tengborn L, Wacey A, Cooper DN. Three novel PROC gene lesions causing protein C deficiency. Clin Genet 1998: 54: 231–233. 0 Munksgaard, 1998
Missense mutations. three of them novel (Am210→Val, Asn248→ Ile, Ah355→Val), were found in the protein c ( PROC ) genes of 7 patients with inherited protein C deficiency associated with venous thrombosis. Comparison with the phenotypic effects of mutations in the analogous residues of factor IX causing hdernophilia B and the use of molecular modelling has provided explanations as to how these lesions might alter either the structure, function or secretion of the protein C molecules encoded.