Hippocampal pathology in refractory temporal lobe epilepsy: T2-weighted signal change reflects dentate gliosis.

BACKGROUND: The MR and pathologic features of hippocampal sclerosis (HS) are well described and include volume decrease and T2-weighted signal increase for MRI, and neuron cell loss and gliosis for pathology. OBJECTIVE: To confirm the established correlation between hippocampal volumes and neuron cell counts, and to study the still controversial association between signal change and gliosis. METHODS: The authors studied 44 patients (22 men and 22 women; mean age at surgery, 37 years) with refractory temporal lobe epilepsy. Quantitative assessment of hippocampal volumes and T2 relaxometry, and neuron and glial cell count in the region CA1 and molecular layer of the dentate gyrus was performed. The proportion of glial fibrillary acidic protein (GFAP)-positive glial cells (reactive astrocytes) was indicated. RESULTS: In a stepwise regression, the ipsilateral hippocampal volume was predicted best by the neuron cell count in the dentate gyrus (p = 0.005, r = 0.4). Hippocampal T2 time, however, was predicted best by the glial cell count in the dentate gyrus (p = 0.01, r = 0.4). None of the other cell counts contributed to either model. In the dentate, 31% of the glial cells were reactive astrocytes, whereas in CA1, 5% were reactive. CONCLUSION: The results confirmed the correlation between hippocampal volumes and neuron cell counts. T2-weighted signal increase in the hippocampus was mainly influenced by gliosis in the dentate gyrus, where a high proportion of glial cells show abnormal activity. This activity may reflect changes important in the development of hippocampal epileptogenicity.     

Norepinephrine modulates glutamatergic transmission in the bed nucleus of the stria terminalis.

The bed nucleus of the stria terminalis (BNST) and its adrenergic input are key components in stress-induced reinstatement and maintenance of drug use. Intra-BNST injections of either beta-adrenergic receptor (beta-AR) antagonists or alpha2-adrenergic receptor (alpha2-AR) agonists can inhibit footshock-induced reinstatement and maintenance of cocaine- and morphine-seeking. Using electrophysiological recording methods in an in vitro slice preparation from C57/Bl6j adult male mouse BNST, we have examined the effects of adrenergic receptor activation on excitatory synaptic transmission in the lateral dorsal supracommissural BNST (dBNST) and subcommissural BNST (vBNST). Alpha2-AR activation via UK-14,304 (10 microM) results in a decrease in excitatory transmission in both dBNST and vBNST, an effect predominantly dependent upon the alpha2A-AR subtype. Beta-AR activation via isoproterenol (1 microM) results in an increase in excitatory transmission in dBNST, but not in vBNST. Consistent with the work with receptor subtype specific agonists, application of the endogenous ligand norepinephrine (NE, 100 microM) elicits two distinct effects on glutamatergic transmission. In dBNST, NE elicits an increase in transmission (62% of dBNST NE experiments) or a decrease in transmission (38% of dBNST NE experiments). In vBNST, NE elicits a decrease in transmission in 100% of the experiments. In dBNST, the NE-induced increase in synaptic transmission is blocked by beta1/beta2- and beta2-, but not beta1-specific antagonists. In addition, this increase is also reduced by the alpha2-AR antagonist yohimbine and is absent in the alpha2A-AR knockout mouse. In vBNST, the NE-induced decrease in synaptic transmission is markedly reduced in the alpha2A-AR knockout mouse. Further experiments demonstrate that the actions of NE on glutamatergic transmission can be correlated with beta-AR function.     

Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial.

Specific receptors for vitamin D have been identified in human muscle tissue. Cross-sectional studies show that elderly persons with higher vitamin D serum levels have increased muscle strength and a lower number of falls. We hypothesized that vitamin D and calcium supplementation would improve musculoskeletal function and decrease falls. In a double-blind randomized controlled trial, we studied 122 elderly women (mean age, 85.3 years; range, 63-99 years) in long-stay geriatric care. Participants received 1200 mg calcium plus 800 IU cholecalciferol (Cal+D-group; n = 62) or 1200 mg calcium (Cal-group; n = 60) per day over a 12-week treatment period. The number of falls per person (0, 1, 2-5, 6-7, >7 falls) was compared between the treatment groups. In an intention to treat analysis, a Poisson regression model was used to compare falls after controlling for age, number of falls in a 6-week pretreatment period, and baseline 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations. Among fallers in the treatment period, crude excessive fall rate (treatment - pretreatment falls) was compared between treatment groups. Change in musculoskeletal function (summed score of knee flexor and extensor strength, grip strength, and the timed up&go test) was measured as a secondary outcome. Among subjects in the Cal+D-group, there were significant increases in median serum 25-hydroxyvitamin D (+71%) and 1,25-dihydroxyvitamin D (+8%). Before treatment, mean observed number of falls per person per week was 0.059 in the Cal+D-group and 0.056 in the Cal-group. In the 12-week treatment period, mean number of falls per person per week was 0.034 in the Cal+D-group and 0.076 in the Cal-group. After adjustment, Cal+D-treatment accounted for a 49% reduction of falls (95% CI, 14-71%; p < 0.01) based on the fall categories stated above. Among fallers of the treatment period, the crude average number of excessive falls was significantly higher in the Cal-group (p = 0.045). Musculoskeletal function improved significantly in the Cal+D-group (p = 0.0094). A single intervention with vitamin D plus calcium over a 3-month period reduced the risk of falling by 49% compared with calcium alone. Over this short-term intervention, recurrent fallers seem to benefit most by the treatment. The impact of vitamin D on falls might be explained by the observed improvement in musculoskeletal function.     

Molecular comparison of the fibre proteins of bovine adenovirus subtype A and subtype B

The fibre gene of the bovine adenovirus type 2 (BAdV2) subtype B was prepared for sequencing by using cloning, sub-cloning and PCR amplification techniques. The nucleotide sequence of the total fibre gene was determined, and it was found to consist of 1,647 nucleotides, coding for a polypeptide of 549 amino acids. The fibre gene regions of BAdV2 A and B subtypes were aligned. The nucleotide identity of the total fibre gene was found to be 60.5%; however, the homology showed great differences in the different subregions coding for the shaft and knob part of the fibre, and the two subtypes were almost identical in the tail subregion. Remarkable changes indicating deletion, insertion and point mutations were found in the shaft subregion when BAdV2/A and B subtypes were compared. We concluded that the differences found in the haemagglutinating activity of the two subtypes of BAdV2 can mostly be explained by the changes in the polypeptide structure of the fibre shaft.     

Effects of TGFbeta on bone ingrowth in the presence of polyethylene particles

We implanted bone harvest chambers (BHCs) bilaterally in ten mature male New Zealand white rabbits. Polyethylene particles (0.3+/-0.1 microm in diameter, 6.4 x 10(12) particles/ml) were implanted for two, four or six weeks bilaterally in the BHCs, with subsequent removal of the ingrown tissue after each treatment. In addition to the particles, one side also received 1.5 microg of recombinant transforming growth factor beta1 (TGFbeta1). At two weeks, the bone area as a percentage of total area was less in chambers containing TGFbeta compared with those with particles alone (7.8+/-1.3% v 16.9+/-2.7% respectively; 95% confidence interval (CI) for difference -14.0 to -4.30; p = 0.002). At four weeks, the percentage area of bone was greater in chambers containing TGFbeta compared with those with particles alone (31.2+/-3.4% v 22.5+/-2.0% respectively; 95% CI for difference 1.0 to 16.4; p = 0.03). There were no statistical differences at six weeks, despite a higher mean value with TGFbeta treatment (38.2+/-3.9% v 28.8 +/-3.5%; 95% CI for difference -4.6 to 23.3; p = 0.16). The number of vitronectin-receptor-positive cells (osteoclast-like cells) was greater in the treatment group with TGFbeta compared with that with particles alone; most of these positive cells were located in the interstitium, rather than adjacent to bone. TGFbeta1 is a pleotropic growth factor which can modulate cellular events in the musculoskeletal system in a time- and concentration-dependent manner. Our data suggest that there is an early window at between two and six weeks, in which TGFbeta may favourably affect bone ingrowth in the BHC model. Exogenous growth factors such as TGFbeta may be a useful adjunct in obtaining osseointegration and bone ingrowth, especially in revisions when there is compromised bone stock and residual particulate debris.     

Risk of recurrence in major central nervous system malformations between 1976 and 2005

OBJECTIVE: The goal of the current publication is to review isolated central nervous system malformations (CSMs) using a database in excess of 75 000 cases, with special regard to the risk of recurrence of these malformations alone or in combination. METHODS: In the period between 1 January 1976 and 31 December 2005, among the 75 320 documented cases, consultations were requested due to earlier isolated CSMs in the patients' histories in 3030 cases (4.2%). Processing the data we only considered disorders of genetic origin, and that was why we excluded the cases due to intrauterine infection. Monogenically inherited malformations were also excluded from the analysis. The diagnosis of the malformations was based on the prenatal diagnosis of ultrasonography as well as the findings of the foetopathological examination. RESULTS: In 65% of the cases, the couples sought counselling because of malformation in a previous pregnancy. In these cases, the risk of recurrence was thought to be 5.2%, while in the case of two affected children this figure stood at 21.9%. Analysing the values for the risk of recurrence in 5-year periods, neural tube defects (NTDs) (particularly anencephaly and spina bifida) showed a detectable decrease, which could be attributed to a growing use of folic acid supplementation around the time of conception and during pregnancy. CONCLUSION: There is a clear decrease of risk of recurrence of NTDs, while in the case of the other CSMs in this study, there is no noteworthy chronological change in their risk of recurrence.     

Prediction of iron deficiency in chronic inflammatory rheumatic disease anaemia

Summary. We prospectively studied 45 anaemic patients (3 7 women, 8 men) with chronic inflammatory rheumatic diseases. The combination of serum ferritin and CRP (as well as ESR) in its predictive capacity for bone marrow iron stores was examined. The relationship between other iron-related measurements (transferrin, transferrin saturation, soluble transferrin receptor, erythrocyte porphyrins and percentage of hypochromic/microcytic erythrocytes) and bone marrow iron stores was also investigated. Stainable bone marrow iron was taken as the most suitable standard to separate iron-deficient from iron-replete patients. 14 patients (31%) were lacking bone marrow iron. Regression analysis showed a good correlation between ferritin and bone marrow iron (adjusted R ²=0.721, P<00001). The combination of ferritin and CRP (ESR) did not improve the predictive power for bone marrow iron (adjusted R ²=0.715) in this cohort of patients with low systemic inflammatory activity. With respect to the bone marrow iron content the best predictive cut-off value of ferritin was 30μg/l (86% sensitivity, 90% specificity). The other iron-related parameters both individually and when combined were less powerful in predicting bone marrow iron than ferritin alone. Only zinc bound erythrocyte protoporphyrin in combination with ferritin slightly improved prediction (adjusted R ²=0.731). A cut-off point of 11% hypochromic erythrocytes reached a high specificity (90%), but was less sensitive (77%).