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.     

Synergistic effect of low dose Cyclosporine A and human interleukin 10 overexpression on acute rejection in rat lung allotransplantation

Objective: Electroporation mediated transfer of plasmid DNA into peripheral muscle results in high transfection efficiency. The aim of this study was to investigate the effect of gene transfer of human IL-10 (hIL-10) into the tibialis anterior muscle (MTA) in combination with low dose Cyclosporine A (CsA) on acute rejection of lung allografts in the rat. Methods: Lung allotransplantation was performed from male BN donor to male Fisher F344 rats. Gene transfer was achieved by intramuscular injection into the MTA of the recipient followed by electroporation (4×20 ms impulses at 200 V/cm) 24 h prior to the transplantation. Group A (n=5) received CsA (2.5 mg/kg bw ip) for 5 days post-transplant and group B (n=5) 2.5 μg of PCIK hIL-10 (plasmid expression vector containing human CMV immediate early gene promoter and enhancer) and a low dose CsA (2.5 mg/kg bw i.p.). Graft function was assessed by blood gas at day 5 after exclusion of the native lung. Animals were sacrificed and blood was drawn to measure serum hIL-10 levels (ELISA) and tissue was sampled for histological grading of rejection. Results: Local expression of hIL-10 was confirmed at the mRNA level by in situ hybridization. All group A control animals showed severe signs of rejection. At day 5 all grafts in group B showed good gas exchange mean PaO2 233±123 mmHg, vs 44±8 mmHg in group A. Histological examination revealed moderate to severe rejection in all animals in group A (IIIB, ISHLT) in contrast to low moderate rejection in group B (II–IIIA). hIL-10 serum levels on day 5 were 14±7 pg/ml in group B vs. 0 in group A. Conclusions: Electroporation mediated hIL-10 overexpression in a peripheral muscle of the recipient in combination with low dose CsA reduces acute rejection in this model of rat lung allotransplantation.     

Small bowel transplantation in the rat: impact of various immunosuppressive regimens on graft-versus-host reaction.

The effect of ciclosporin (CS) and methotrexate (MTX) on the development of graft-versus-host (GvH) disease was examined after small bowel allotransplantation in the rat. The drugs were tested either alone or in combination. Lewis small bowel allografts were transplantated into Brown Norway recipients in a heterotopic position. The native small bowel, spleen, liver, skin, mesenteric lymph nodes and the kidney of the recipients were examined histologically 5, 10 and 20 days after allotransplantation. Intraepithelial lymphocyte numbers were determined quantitatively in the native small bowel. The relative spleen weight of the host was determined after sacrifice for estimation of the severity of GvH disease. Grade I GvH reaction of the native small bowel occurred in the animals without immunosuppression, but graft rejection predominated in this group. Treatment with CS was effective in the early postoperative periods; after 10 and 20 days GvH lesions in the native small bowel were comparable to those observed in the allogeneic combinations. MTX had a detrimental effect on the allografts and the GvH reaction was augmented. When CS and MTX were combined, GvH lesions were comparable to those in the animals treated solely with CS. Animals, however, suffered from heavy side effects. The spleen, liver, lymph nodes and kidney exhibited only unspecific histologic changes, which could not unequivocally be recognized as a GvH reaction. This was true for all groups. As a conclusion it can be said that GvH reaction occurs in the early postoperative period in a fully allogeneic model and cannot be prevented by CS in the dosae used. MTX was not seen to be of any value in this regard.     

The deficiency model: an exploration of current approaches to late-life disorders.

Many of the terms used to describe conditions in elderly individuals, whether medical (deterioration, involution, degeneration) or neurobehavioral (impairment, dysfunction), imply deficiency. The complex of distorted views of real impairment, illness, or disability may be described as the deficiency model. Although developmental theory has expanded explosively and could offer an alternative frame of reference to dispel denigration of the elderly condition, late life continues to be viewed as lacking all redeeming aspects, while mortality is considered an obstacle to prolonging life rather than one of its determinants. Deficiency-model thinking has influenced the conduct of epidemiologic, neurobiologic and clinical research, whose results in turn have often been interpreted to reinforce such thinking. It can also distort clinical approaches to diagnosis and treatment of late-life disorders. This paper offers instead an alternative approach that focuses on late life as a developmental task.     

The effect of spinal manipulation on pain and prostaglandin levels in women with primary dysmenorrhea.

OBJECTIVE: The primary objectives of this study were to compare the effect of spinal manipulation vs. sham manipulation on a) circulating plasma levels of the prostaglandin F2a metabolite, 15-keto-13,14-dihydroprostaglandin (KDPGF2a), b) perceived abdominal and back pain and c) perceived menstrual distress in women with primary dysmenorrhea. DESIGN: This randomized clinical pilot study investigated the outcome measures before and after either a spinal manipulation treatment (SMT) or a sham manipulation. SETTING: All subjects were treated at the National College Chiropractic clinic, a private chiropractic clinic in the suburban Chicago area. PARTICIPANTS: Forty-five women with a history of primary dysmenorrhea were recruited from the local community. The volunteers ranged in age from 20-49 (mean age = 30.3 yr), and were entered into the study between April 1990 and January 1991. Twenty-four were randomly assigned to the spinal manipulation group and 21 were assigned to the sham group. INTERVENTIONS: Subjects treated with spinal manipulation were placed in a side-lying position with the bottom leg straight and the top leg flexed at the knee and hip. They received a high-velocity, short lever, low-amplitude thrust to all clinically relevant vertebral levels within T10 and L5-S1 and the sacroiliac joints. In the sham manipulation, subjects were placed in a side-lying position with both hips and knees flexed. Their manipulation consisted of a similar thrust administered to the midline base of the sacrum. OUTCOME MEASURES: Perceived abdominal and back pain were measured with a visual analog scale, and menstrual distress was measured with the Menstrual Distress Questionnaire. Both were administered 15 min before and 60 min after treatment. Blood samples were collected by venipuncture for the determination of plasma levels of KDPGF2a at the same times. The plasma was then assayed for KDPGF2a by radioimmunoassay. RESULTS: Analysis of covariance and paired Student's t tests were used for the statistical evaluation. Immediately after treatment, the perception of pain and the level of menstrual distress were significantly reduced by SMT. This reduction was associated with a significant reduction in plasma levels of KDGPF2a in the SMT group. A significant and similar reduction in plasma KDPGF2a also occurred in the sham group, indicating that a placebo effect was associated with a single sham intervention. CONCLUSIONS: This randomized pilot study suggests that SMT may be an effective and safe nonpharmacological alternative for relieving the pain and distress of primary dysmenorrhea. However, the large change in KDPGF2a observed in both treatment groups clearly indicates that further studies with more subjects, studied over a longer time frame, are needed to resolve the question of a placebo effect.     

Imaging of activated microglia with PET and [11C]PK 11195 in corticobasal degeneration.

Positron emission tomography (PET) using [(11)C]PK 11195, a ligand for peripheral benzodiazepine receptor binding sites, offers the opportunity to image activated microglia in vivo. This tool may therefore be used to display the occurrence of microglial activation in the course of neurodegeneration. A patient with the clinical diagnosis of corticobasal degeneration (CBD) and left-sided symptoms was studied using fluorodeoxyglucose (FDG) and [(11)C]PK 11195 PET. We found a marked right hemispheric hypometabolism and asymmetric microglial activation in corresponding areas of the basal ganglia and right temporal and parietal cortex. [(11)C]PK 11195 PET suggests involvement of microglial activation in the pathogenesis of CBD.