An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene

The gene for autosomal recessive spinal muscular atrophy (SMA) has been mapped to 5q12 in a region that contains repeated markers and genes. Three cDNAs that detect deletions in SMA patients have been reported. One of these, the survival motor neuron (SMN) cDNA, is encoded by two genes (SMNT and SMNC) which are distinguished by base changes in exons 7 and 8. Exon 7 of the SMNT gene is not detectable in approximately 95% of SMA cases, due either to deletion or sequence conversion. There is limited information on the mutations in SMA patients that have detectable SMNT, these are critical for confirmation of SMNT as the SMA gene. Using SSCP analysis of the SMN exons we screened our SMA patients that possess at least one intact SMNT allele for mutations in SMNT. We identified one type I SMA patient with an 11 bp duplication in exon 6 which causes a frameshift and premature termination of the deduced SMNT protein. Dosage and SSCP analysis of SMNT in this family indicated that the father contributed a SMNT-deleted allele to the affected child whereas the mother passed on the 11 bp exon 6 duplication SMNT allele. Analysis of RNA by RT-PCR conclusively demonstrated that the 11 bp duplication is associated with the SMNT locus and not SMNC. This mutation provides strong support for SMN as the SMA-determining gene and indicates that disruption of SMNT on its own is sufficient to produce a severe type I SMA phenotype.      

Age-related galactosylation of the N-linked oligosaccharides of human serum IgG

In a study of 151 normal, healthy individuals of both sexes varying in age from 1-70 yr, it was found that the relative incidence of agalactosyl (with both outer arms terminating in N-acetylglucosamine) N-linked oligosaccharides on total serum IgG decreased from birth to a minimum (at 25 yr of age) and then increased with age. The relative incidence of digalactosyl structures varied inversely to this, and the relative incidence of monogalactosyl structures was constant. Galactosylation of the N-linked oligosaccharides of the human serum IgG of normal individuals is therefore an age-related molecular parameter. Several reports have suggested that rheumatoid arthritis is associated with a decreased galactosylation of serum IgG (3-5). The normal variation in galactosylation with age as described here allows a true assessment of disease-associated changes in this parameter, and raises the possibility that one of the lesions in rheumatoid arthritis is an accelerated aging of the immune system. In addition, heterogeneity within age groups may be due to intrinsic differences in genetic endowment, or may reflect the impact of extrinsic factors (8).     

Impact of improved glycaemic control on rates of hypoglycaemia in insulin dependent diabetes mellitus

Increased emphasis on strict glycaemic control of insulin dependent diabetes mellitus (IDDM) in young patients may be expected to cause increases in rates of significant hypoglycaemia. To evaluate whether this is the case for a large population based sample of IDDM children and adolescents rates of severe (coma, convulsion) and moderate (requiring assistance for treatment) hypoglycaemia were studied prospectively over a four year period. A total of 709 patients were studied yielding 2027 patient years of data (mean (SD) age: 12.3 (4.4); range 0-18 years, duration IDDM: 4.9 (3.8) years). Details of hypoglycaemia were recorded at clinic visits every three months when glycated haemoglobin (HbA1c) was also measured. Overall the incidence of severe hypoglycaemia was 7.8 and moderate was 15.4 episodes/100 patient years. Over the four years mean (SD) clinic HbA1c steadily fell from 10.2 (1.6)% in 1992 to 8.8 (1.5)% in 1995. In parallel with this there was a dramatic increase in the rate of hypoglycaemia, especially in the fourth year of the study, when severe hypoglycaemia increased from 4.8 to 15.6 episodes/100 patient years. This increase was particularly marked in younger children (< 6 years) in whom severe hypoglycaemia increased from 14.9 to 42.1 episodes/100 patient years in 1995. It is concluded that attempts to achieve improved metabolic control must be accompanied by efforts to minimise the effects of significant hypoglycaemia, particularly in the younger age group.     

Evaluation of the Merlin,Micronaut System for Automated Antimicrobial Susceptibility Testing of<Emphasis Type="Italic"> Pseudomonas aeruginosa</Emphasis> and<Emphasis Type="Italic"> Burkholderia</Emphasis> Species Isolated from Cystic Fibrosis Patients

Since accurate antimicrobial susceptibility testing of bacterial cystic fibrosis isolates is known to be problematic and an optimal in vitro testing method has not yet been evaluated, the study presented here was conducted to compare the performance of the reference agar dilution method and broth microdilution with a commercially available automated susceptibility test system (Merlin; Micronaut, Germany). In this pilot study, the susceptibility of 70 clinical strains of Pseudomonas aeruginosa and Burkholderia cepacia-like organisms to nine antimicrobial agents was tested using these methods. Susceptibility results generated by broth microdilution (both automated and according to the National Committee for Clinical Laboratory Standards recommendations) were demonstrated to be of good reproducibility, and they compared favourably to the time- and material-consuming standard agar dilution reference method, especially after a prolonged incubation time (48 h).     

Inositol phosphoglycan P-type in healthy and preeclamptic pregnancies

An association between inositol phosphoglycan P-type (P-IPG) and preeclampsia has been demonstrated over recent years. This molecule can mediate many of the metabolic and growth promoting effects of insulin. Dysregulation of the mediator family is associated with insulin resistance. An increased concentration of P-IPG has been reported in preeclamptic placenta, although its precursor (GPI) was undetectable in those placental samples. Insulin administration, that induces P-IPG release in normal human placenta, was shown not to cause production/release of the mediator from preeclamptic placental tissue as a consequence of a disturbed insulin signalling. Amniotic fluid is enriched of this mediator, with further increase during preeclampsia. We have found that the fetus released increasing amounts of P-IPG in the urine between 13 and 18 weeks of gestation, reaching a plateau beyond 20 weeks. Cord blood of infants of preeclamptic mothers showed an increased content of soluble P-IPG compared to controls and to the mother.     

药物代谢分型的研究进展

目的：为了促进药物代谢分型研究在临床上的深放。方法：综述近几年具遗传多态性代谢酶的探针药物、代谢分型方法以及影响因素。介绍“Cooktail”分型法。比较代谢分型与基因分型两种分型方法。结果:疾病、并用药物、探药剂量、样本处理方法、服药依从性是代谢分型的主要影响因素。结论：药物代谢分型能指导临床安全合理有效地用药。基因分型与代谢分型各有优点,应灵活应用。“Cooktail”分型方法具有独特的优越性和发展前景,应大力开展在特殊群体中的代谢分型研究。     

PMD6 Chronic Care Costs of New Medicare HMO Enrollees: Implications for Disease Management

Cost-effective care for chronic conditions is a growing concern of health plans enrolling increasing numbers of the elderly and disabled under Medicare risk contracts. This study provides evidence of the prevalence, patterns of care, and costs of chronic illnesses among new Medicare HMO enrollees. The results provide a foundation for estimates of the cost-effectiveness of drug therapy and care management programs that serve this group.
METHODS: We used national Medicare claims data to examine chronic care services and associated costs for a sample of 19,084 beneficiaries who enrolled in an HMO in 1995. We constructed three measures of cost: the total Medicare-covered cost, the cost of medical claims with the chronic condition coded as a diagnosis, and the regression-estimated effect of the chronic condition on cost.
RESULTS: 58% of the new Medicare HMO enrollees in our sample were treated for at least one of the selected chronic conditions in the six months before enrollment. One-third of the new enrollees had multiple conditions represented by diagnoses in more than one of eighteen chronic-condition groups. Persons with chronic conditions accounted for 93% of pre-enrollment Medicare costs among new HMO enrollees. Per 1,000 enrollees, pre-enrollment Medicare costs were greatest for those with hypertensive disease, coronary heart disease, heart failure, and diabetes.
CONCLUSIONS: The concentration of utilization and costs in those with chronic conditions suggests that appropriate drug therapy and care management for those with chronic conditions should be a top priority for HMOs with Medicare risk contracts. These estimates of prevalence suggest a need for HMOs to screen new Medicare HMO enrollees for chronic conditions immediately upon enrollment to ensure continuity of care.     

The Human Brain Age 7-11 Years: A Volumetric Analysis Based on Magnetic Resonance Images

Volumetric magnetic resonance image (MRI)-based morphometrywas performed on the brains of 30 normal children (15 malesand 15 males) with a mean age of 9 years (range 7–11 years).This age range lies in a late but critical phase of brain growthwhere net volumetric increment will be small but when the detailsof brain circuit are being fine-tuned to support the operationsof the adult brain. The brain at this age is 95% the volumeof the adult brain. The brain of the female child is 93% thevolume of the male child. For more than 95% of brain structures,the volumetric differences in male and female child brain areuniformly scaled to the volume difference of the total brainin the two sexes. Exceptions to this pattern of uniform scalingare the caudate, hippocampus and pallidum, which are disproportionatelylarger in female than male child brain, and the amygdala, whichis disproportionately smaller in the female child brain. Thepatterns of uniform scaling are generally sustained during thefinal volumetric increment in overall brain size between age1–11 and adulthood. There are exceptions to this uniformscaling of child to adult brain, and certain of these exceptionsare sexually dimorphic. Thus, with respect to major brain regions,the cerebellum in the female but not the male child is alreadyat adult volume while the brainstem in both sexes must enlargemore than the brain as a whole. The collective subcortical graymatter structures of the forebrain of the female child are alreadyat their adult volumes. The volumes of these same structuresin the male child, by contrast, are greater than their adultvolumes and, by implication, must regress in volume before adulthood.The volume of the central white matter, on the other hand, isdisproportionately smaller in female than male child brain withrespect to the adult volumes c cerebral central white matter.By implication, relative volumetric increase of cerebral centralwhite matter by adulthood must be greater in the female thanmale brain. The juxtaposed progressive and regressive patternsof growth of brain structures implied by these observationsin the human brain have a soundly established precedent in thedeveloping rhesus brain. There is emerging evidence that sexuallydimorphic abnormal regulation of these terminal patterns ofbrain development are associated with gravely disabling humandisorders of obscure etiology.     

The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase

1. Propofol (2,6-diisopropylphenol) is widely used as a general anesthetic and for the maintenance of long-term sedation. We have tested the hypothesis that propofol alters endocannabinoid brain content and that this effect contributes to its sedative properties. 2. A sedating dose of propofol in mice produced a significant increase in the whole-brain content of the endocannabinoid, N-arachidonylethanolamine (anandamide), when administered intraperitoneally in either Intralipid or emulphor-ethanol vehicles. 3. In vitro, propofol is a competitive inhibitor (IC(50) 52 micro M; 95% confidence interval 31, 87) of fatty acid amide hydrolase (FAAH), which catalyzes the degradation of anandamide. Within a series of propofol analogs, the critical structural determinants of FAAH inhibition and sedation were found to overlap. Other intravenous general anesthetics, including midazolam, ketamine, etomidate, and thiopental, do not affect FAAH activity at sedative-relevant concentrations. Thiopental, however, is a noncompetitive inhibitor of FAAH at a concentration of 2 mM. 4. Pretreatment of mice with the CB(1) receptor antagonist SR141716 (1 mg kg(-1), i.p.) significantly reduced the number of mice that lost their righting reflex in response to propofol. Pretreatment of mice with the CB(1) receptor agonist, Win 55212-2 (1 mg kg(-1), i.p.), significantly potentiated the loss of righting reflex produced by propofol. These data indicate that CB(1) receptor activity contributes to the sedative properties of propofol. 5. These data suggest that propofol activation of the endocannabinoid system, possibly via inhibition of anandamide catabolism, contributes to the sedative properties of propofol and that FAAH could be a novel target for anesthetic development.