Double anterograde tracing of outputs from adjacent "barrel columns" of rat somatosensory cortex. Neostriatal projection patterns and terminal ultrastructure

The sensory input to the neostriatum from groups of cortical cells related to individual facial vibrissae has been investigated at both light- and electron-microscopic resolution. The purpose of the study was to establish the extent to which corticostriatal input maintains the anatomical coding of spatial information that is present in cortex. A double anterograde tracing method was used to identify the output projections from groups of adjacent neurons in different barrel columns, so that the anatomical relationships between two groups could be studied throughout their length. Adjacent whiskers are represented in adjoining cortical barrels and an examination of corticostriatal projections from these reveals two patterns of projection. In one, the anatomical topography is partially preserved; the barrels are represented in adjoining, discrete, areas of the somatosensory neostriatum. In the second projection pattern, the neostriatal innervation is diffuse and adjacent barrels are represented in overlapping regions of the neostriatum. Moreover, the fibres are thinner, have smaller boutons, and are present in both the ipsilateral and contralateral neostriatum. The two systems also enter the neostriatal neuropile separately. The discrete topographic system enters the adjacent neostriatum as collaterals which leave the descending corticofugal fibres at right angles, while the diffuse system enters directly from the corpus callosum at an acute angle. Examination of the neostriatal terminal fields by correlated light and electron microscopy, shows that characteristic axospinous terminals on spiny neurons are made by both groups of cortical fibres, although they differ in their size and morphology. It is concluded that at least two corticostriatal pathways arise from the barrel cortex. One connection maintains some of the anatomical code implicit in the barrel pattern of primary somatosensory cortex, but another, more diffuse, system is overlaid upon it which may carry different information from this complex area of cortex.     

Influence of frequency of atrial contraction on coronary blood flow and ventricular performance in the conscious dog with myocardial infarction.

The effects of alterations in the frequency of contraction on coronary blood flow and ventricular performance were studied in 12 conscious, unsedated dogs with established myocardial infarction. Total and regional coronary blood flow was measured using radioactive microspheres. The peak increase in flow to the right ventricle was 71% to the infarcted area of the left ventricle was 72% to the non-infarcted area of the left ventricle was 90% and to the ventricular septum was 104%. Despite the generalized increases in regional myocardial blood flow, flow tended to decrease to the subendocardial portion of the infarcted area of the left ventricle. The peak increases in coronary flow and the reduction in flow to the subendocardial portion of the infarcted area occurred at a heart rate of approximately 200/min provided by atrial pacing. Myocardial contractility, as evidenced by peak increases of 16% in maximum LV dP/dt and 12% in dP/dtP, was only enhanced with abrupt incremental changes in heart rate and not with continuous atrial pacing over 15-min periods. Despite the generalized increases in coronary perfusion coronary sinus oxygen content decreased with a widening of the coronary arteriovenous oxygen difference indicating increased myocardial oxygen usage. Thus increasing frequency of contraction in myocardial infarction results in a slight initial but not sustained inotropic effect, a moderate and generalized increase in regional myocardial blood flow, increased myocardial oxygen consumption, and the potential for subendocardial extension of the area of myocardial damage within the infarcted area.     

Investigation of within-study selective reporting in clinical research: follow-up of applications submitted to a local research ethics committee

Rationale, aims and objectives Within‐study selective reporting is widely believed to exist, although to date there have been no empirical studies to assess the extent of the problem in clinical research. The present study aimed to examine this process. Methods We undertook a pilot study, involving a single local research ethics committee (LREC), in which we compared the outcomes, analysis and sample size proposed in the original approved study protocol with the results presented in the subsequent study report. Results We received 41 (73%) replies from lead researchers of 56 projects, which were a complete cohort of clinical research applications approved in a particular time period by the LREC. Fifteen of these projects, which were completed and published at the time of our study, were further investigated. Only six (40%) stated which outcome variables were of primary interest and four (67%) of these showed consistency in the reports. Eight (53%) of the 15 studies mentioned an analysis plan. However, seven (88%) of these eight studies did not follow their prescribed analysis plan: the analysis of outcome variables or associations between certain variables were found to be missing from the report. Conclusions Our pilot study has shown that within‐study selective reporting may be examined qualitatively by comparing the study report with the study protocol. Our results suggest that it might well be substantial; however, the bias can only be broadly identified as protocols are not sufficiently precise.     

Cryopreservation of all prezygotes in patients at risk of severe hyperstimulation does not eliminate the syndrome, but the chances of pregnancy are excellent with subsequent frozen-thaw transfers

In-vitro fertilization patients (n = 15) at risk of ovarian hyperstimulation syndrome (OHSS) (oestradiol > or =4500 pg/ml on the day of human chorionic gonadotrophin administration and 25 or more follicles of intermediate or large size) underwent aspiration of all follicles and cryopreservation of all fertilized oocytes at the pronuclear stage. Patients were monitored for up to 2 weeks post- retrieval. Subsequent transfer of cryopreserved-thawed embryos was performed in programmed cycles using exogenous oestrogen and progesterone for endometrial preparation. Two patients (13%) developed OHSS necessitating hospitalization and vaginal aspiration of ascitic fluid. Two other patients (13%) developed moderate OHSS requiring ascitic fluid vaginal aspiration in the office setting, with dramatic improvement of the condition. Subsequent transfer of cryopreserved- thawed embryos yielded a clinical pregnancy rate of 58% per transfer and ongoing or delivery rates of 42 and 67% per transfer and per patient respectively. By eliminating pregnancy potential with cryopreservation of all prezygotes and examining the pregnancy potential with subsequent cryopreserved-thawed transfers, it is concluded that OHSS is reduced, but not eliminated for patients at risk. Subsequent transfer of cryopreserved-thawed prezygotes in a programmed cycle with exogenous steroids yields an excellent pregnancy rate.      

Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene

Plasma amyloid beta protein (Abeta42) levels and late onset Alzheimer's disease (LOAD) have been linked to the same region on chromosome 10q. The PLAU gene within this region encodes urokinase-type plasminogen activator, which converts plasminogen to plasmin. Abeta aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Abeta. We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Abeta42 and LOAD. PLAU SNP compound genotypes composed of haplotype pairs showed significant association with AD in three independent case-control series. PLAU SNP haplotypes associated significantly with plasma Abeta42 in 10 extended LOAD families. One of the SNPs analyzed was a missense C/T polymorphism in exon 6 of PLAU (PLAU_1=rs2227564), which causes a proline to leucine change (P141L). We analyzed PLAU_1 for association with AD in six case-control series and 24 extended LOAD families. The CT and TT PLAU_1 genotypes showed association (P=0.05) with an overall estimated odds ratio of 1.2 (1.0-1.5). The CT and TT genotypes of PLAU_1 were also associated with significant age-dependent elevation of plasma Abeta42 in 24 extended LOAD families (P=0.0006). In knockout mice lacking the PLAU gene, plasma--but not brain--Abeta42 as well as Abeta40 was significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found among plasma Abeta42, LOAD and variants in the IDE or VR22 region. These results provide strong evidence that PLAU or a nearby gene is involved in the development of LOAD. PLAU_1 is a plausible pathogenic mutation that could act by increasing Abeta42, but additional biological experiments are required to show this definitively.     

Trisomy 15 mosaic derived from trisomic conceptus: Report of a case and a review

We report on a fetus with 47,XX,+15 chromosome abnormality detected on chorionic villus sampling (CVS). The pregnancy was terminated at 15.5 weeks of gestation and chromosome analysis done on amniocytes and fetal tissues showed a karyotype 46,XX/47,XX,+15. Autopsy showed multiple abnormalities. Short-arm polymorphisms of the three number 15 chromosomes were highly informative in the delineation of parental origin and the stage of meiotic error. Using fluorescent in situ hybridization (FISH) with D15Z1 and a chromosome 15 painting probe, in addition to DA/DAPI and G-banding, we were able to show that the trisomic conceptus was derived through maternal meiosis I error. The trisomic state was then partially corrected by the loss of one of the two maternal 15s resulting in mosaicism without uniparental disomy (UPD). Striking differences in the proportion of trisomic cells in kidneys, blood, intestine, and skin, and lower proportions of trisomic cells in transformed and frozen than in fresh tissues, illustrate the continuing cell selection in this fetus in favour of the normal cell line. Trisomy 15 conceptions are usually aborted spontaneously in the first trimester of pregnancy. The longer survival of this fetus is most probably the result of a chromosome 15 loss from the trisomic zygote. To the best of our knowledge, the presence of this lethal trisomy has been reported in only five live-born infants, and in five fetuses including the present case, it was detected prenatally and the pregnancies were terminated. © 1996 Wiley-Liss, Inc.