Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.      

Speech-controlled generation of radiology reports

Voice entry has been successfully employed to generate radiology reports with a word recognizer with a 1,000-word lexicon capacity. About 50% of reports were able to be dictated with a single 900-word lexicon. This was split into five sections by anatomic or subspecialty application. Each was augmented to 900 words. By switching from one lexicon to another, it was possible to dictate more than 70% of reports. With exclusive use of three lexicons in subspecialty areas (gastrointestinal radiology, neuroradiology, and mammography), and with further modification of the respective vocabulary, it has been possible to employ the system 88% of the time. Twelve percent of cases included wording that was beyond the scope of the lexicon. Computer subsets that allow different translations of some words when used in different contexts have been used. Some of these are used as triggers that will print whole lines, sentences, or even complete reports. Dictation times with voice entry take about 20% longer. Recognition reliability has been greater than 95%.     

Risk factors for development of dehydration in young children with acute watery diarrhoea: a case-control study

In a case-control study to understand the risk factors for development of life-threatening dehydration, a total of 379 children comprising 243 cases (moderate or severe dehydration) and 136 controls (non or mild dehydration) up to 2 years of age suffering from acute watery diarrhoea were studied. By univariate analysis, the presence of vibrios in stool, withdrawal of breast feeding during diarrhoea, not giving fluids, including oral rehydration solution (ORS), during diarrhoea, frequent purging (> 8/ day), vomiting (> 2/day) and undernutrition were identified as risk factors. However, by multivariate analysis after controlling for confounders, withdrawal of breast feeding during diarrhoea (odds ratio (OR) = 6.8, p < 0.00001) and not giving ORS during diarrhoea (OR = 2.1, p < 0.006) were identified as significant risk factors. The confounding variables which also contributed significantly to increasing the risk were age (≤ 12 months; OR = 2.7, p = 0.001), frequent purging (> 8/day; OR = 4.1, p < 0.00001), vomiting (> 2/day; OR = 2.4, p = 0.001) and severe undernutrition (%median <60 weight-for-age of Indian Academy of Paediatrics classification; OR = 3.1, p = 0.001). We feel that these findings will be useful for Global and National Diarrhoeal Diseases Control Programmes for formulating intervention strategies for preventing death due to diarrhoeal dehydration.     

Intracranial abnormalities in infants treated with extracorporeal membrane oxygenation: imaging with US and CT

Findings at neuroimaging in 100 consecutive infants treated with extracorporeal membrane oxygenation (ECMO) are presented. Imaging in these infants consisted of pretreatment cranial ultrasonography (US), daily US studies while on ECMO, and follow-up cranial computed tomography (CT) after treatment. There were findings of abnormalities in 43 patients. Thirty had intracranial bleeding, often of unusual extent and distribution. Thirteen additional infants had nonhemorrhagic abnormalities alone. Bleeding considered to be major was seen in 12% of infants. Large parenchymal hemorrhages and infarcts, cerebellar hemorrhages, and diffuse edema were the most significant abnormalities, with a 50% mortality (eight of 16 patients). No lateralization was noted with respect to distribution of bleeding sites or areas of nonhemorrhagic abnormalities. US was a sensitive but imperfect screening tool for intracranial abnormalities. Abnormalities missed with US included peripheral and small parenchymal lesions, subarachnoid hemorrhage, cerebral atrophy, and sagittal sinus thrombosis.     

Indium-111 labeled platelet deposition following transfemoral angiography

The incidence of thromboembolitic events in patients undergoing transfemoral angiography was examined using indium-111 labeled platelets. Twenty-seven patients received approximately 300 muCi of autologous labeled platelets at least 3 hours before angiography and were scanned with a gamma camera immediately before and after angiography. All patients were free of clinically obvious complications in the 1-2 day period after angiography. Our results showed evidence of platelet deposition at 21 sites other than the puncture site in 12 (44%) patients. Most platelet deposition (54%) occurred along the region between the puncture site and the aortic bifurcation; 24% occurred at sites not traversed by the catheter. At the puncture site itself, there was substantial platelet uptake in 44% of patients. This study indicates the need for further work in determining the most suitable catheter material and in assessing the efficacy of other measures such as anticoagulant or antiplatelet therapy.     

Long-term use of antecubital veins for plasma exchange. The Canadian Cooperative Multiple Sclerosis Study Group

True or sham plasma exchange was done weekly for 20 weeks in patients in two of the randomization groups in a prospective, blind clinical trial of experimental treatments for multiple sclerosis. Because patients could be randomized to receive sham plasma exchange and placebo medications, it was decided when the trial was designed that the use of fistulae, arteriovenous shunts, venous cutdowns, or other aggressive forms of venous access would not be permitted for any patient. Accordingly, patients judged to have inadequate superficial antecubital veins were ineligible for the trial. To date, only 13 (4.4%) of 294 patients considered for entry into the trial have been rejected on these grounds. In only 4 of the 93 patients undergoing exchange was it necessary to discontinue plasma exchange because of inadequate venous access. In 79.3 percent of the 1207 exchanges done in these patients, there were no problems of any kind with venous access. In 5.4 percent of these 1207 exchanges, it was necessary to terminate the procedure prematurely because of difficulties with patients' veins. Thus, the great majority of patients free of serious systemic illness (other than chronic progressive multiple sclerosis) can undergo weekly plasma exchange for up to 20 weeks using superficial antecubital veins without the need to resort to more invasive methods of venous access.     

The Methylazoxymethanol Acetate (MAM-E17) Rat Model: Molecular and Functional Effects in the Hippocampus

Administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM) on embryonic day 17 (E17) produces behavioral and anatomical brain abnormalities, which model some aspects of schizophrenia. This has lead to the premise that MAM rats are a neurodevelopmental model for schizophrenia. However, the underlying molecular pathways affected in this model have not been elucidated. In this study, we investigated the molecular phenotype of adult MAM rats by focusing on the frontal cortex and hippocampal areas, as these are known to be affected in schizophrenia. Proteomic and metabonomic analyses showed that the MAM treatment on E17 resulted primarily in deficits in hippocampal glutamatergic neurotransmission, as seen in some schizophrenia patients. Most importantly, these results were consistent with our finding of functional deficits in glutamatergic neurotransmission, as identified using electrophysiological recordings. Thus, this study provides the first molecular evidence, combined with functional validation, that the MAM-E17 rat model reproduces hippocampal deficits relevant to the pathology of schizophrenia.