PET imaging of brain 5-HT1A receptors in rat in vivo with 18F-FCWAY and improvement by successful inhibition of radioligand defluorination with miconazole.

18F-FCWAY (18F-trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) is useful in clinical research with PET for measuring serotonin 1A (5-HT1A) receptor densities in brain regions of human subjects but has significant bone uptake of radioactivity due to defluorination. The uptake of radioactivity in skull compromises the accuracy of measurements of 5-HT1A receptor densities in adjacent areas of brain because of spillover of radioactivity through the partial-volume effect. Our aim was to demonstrate with a rat model that defluorination of 18F-FCWAY may be inhibited in vivo to improve its applicability to measuring brain regional 5-HT1A receptor densities. METHODS: PET of rat head after administration of 18F-FCWAY was used to confirm that the distribution of radioactivity measured in brain is dominated by binding to 5-HT1A receptors and to reveal the extent of defluorination of 18F-FCWAY in vivo as represented by radioactivity (18F-fluoride ion) uptake in skull. Cimetidine, diclofenac, and miconazole, known inhibitors of CYP450 2EI, were tested for the ability to inhibit defluorination of 18F-FCWAY in rat liver microsomes in vitro. The effects of miconazole treatment of rats on skull radioactivity uptake and, in turn, its spillover on brain 5-HT1A receptor imaging were assessed by PET with venous blood analysis. RESULTS: PET confirmed the potential of 18F-FCWAY to act as a radioligand for 5-HT1A receptors in rat brain and also revealed extensive defluorination. In rat liver microsomes in vitro, defluorination of 18F-FCWAY was almost completely inhibited by miconazole and, to a less extent, by diclofenac. In PET experiments, treatment of rats with miconazole nitrate (60 mg/kg intravenously) over the 45-min period before administration of 18F-FCWAY almost obliterated defluorination and bone uptake of radioactivity. Also, brain radioactivity almost doubled while the ratio of radioactivity in receptor-rich ventral hippocampus to that in receptor-poor cerebellum almost tripled to 14. The plasma half-life of radioligand was also extended by miconazole treatment. CONCLUSION: Miconazole treatment, by eliminating defluorination of 18F-FCWAY, results in effective imaging of brain 5-HT1A receptors in rat. 18F-FCWAY PET in miconazole-treated rats can serve as an effective platform for investigating 5-HT1A receptors in rodent models of neuropsychiatric conditions or drug action.     

STUDIES ON NUTRITION AND PRECANCEROUS LESIONS OF THE ESOPHAGUS IN THE ADOLESCENTS

This paper reports the prevalence of chronic esophagitis and nutritional status among 538 young persons aged 15 to 26 years from the high risk area for esophageal cancer. Of these subjects, 166 were from households with history of esophageal cancer and 372 were from households without history of esophageal cancer. The Incidences of chronic esophagltis among male and female adolescents were 37. 6% and 36% respectively, which was significantly higher than those in the low risk area (17%). The frequency of chronic esophagltis in the adolescents in the households with history of esophageal cancer was aiso higher than in those In the households without history of esophageal cancer. The deficiencies of vitamins, especially of riboflavin and ascorbate, are prevalent and severe among these adolescents. Ascorbate deficiency Is correlated with the severity of the chronic esophagltis. These results indicate that chronic esophagltis may be involved in the natural history of esophageal carclnogenesis. Nutrient defic     

Supratentorial ischemic stroke: more than an upper motor neuron disorder.

The primary goal of this study was to identify secondary functional changes in the peripheral motor units of the paretic upper extremity (UE) in patients with severe ischemic stroke and to determine how these changes develop during the first weeks after stroke. An inception cohort of 27 consecutive patients with an acute ischemic supratentorial stroke and an initial UE paralysis was compared with 10 healthy control subjects. The ulnar nerve was electrically stimulated proximal to the wrist and electromyographic recordings were obtained from the abductor digiti minimi muscle. Hemiparetic side mean values of the compound muscle action potential (CMAP) 1 and 3 weeks after stroke were compared with the nonparetic side and with CMAP values obtained from healthy control subjects. The mean CMAP amplitude in patients was significantly lower on the paretic side compared with the nonparetic side and with control subjects. Decrease in CMAP amplitude was observed in more than half of the stroke patients, sometimes as early as 4 days after stroke, and persisted in most cases. Whenever present, it was accompanied by absence of motor recovery at that specific time after stroke. Decreased CMAP amplitude in the abductor digiti minimi muscle can be seen already in the very acute phases after stroke unrelated to peripheral neuropathy, radiculopathy, or plexopathy, and it is accompanied by absence of UMN recovery. This knowledge is important for interpreting electrophysiological data in stroke patients.     

Infantile autism—fragile X: Molecular findings support genetic heterogeneity

Twenty-two members of 18 families with autism have been examined for the presence of mutations and abnormal methylation in the FMR-1 region at Xq27.3. All patients fulfilled diagnostic criteria of infantile autism. A characteristic pattern of insertion and methylation were detected after Southern blot analysis in 7 autistic individuals expressing the fragile site at Xq27.3. Normal DNA patterns were observed in 15 autistic boys cytogenetically negative for the fragile site. The results indicate a lack of involvement of the FMR-1 region in infantile autists negative for fragile X expression. © 1992 Wiley-Liss, Inc.     

In vivo gene transfer: focus on the kidney

Renal gene transfer techniques are being developed as a novelexperimental approach to understand the pathogenesis of renaldisease and to potentially develop new therapeutic tools. Wereview the currently available technology to introduce foreigngenetic material into renal tissue, i.e., retroviral, adenoviral,and liposomal transfer systems with their respective advantagesand caveats. Today, the transfer efficiency of these methodsappears to be sufficiently high to study the effects of transducedgenes on renal function and morphology in rat kidney. This willallow (i) the elucidation of the function of genes on the courseof renal disease in experimental animal models and (ii) themodulation of local expression of endogenous genes which presumptivelycontribute to renal pathology in these models. One strategyto accomplish this aim is the use of recombinant DNA technologyto design antisense DNA constructs or oligonucleotides, whichinterfere with the renal expression of target genes. We willalso discuss some of the shortcomings of the currently usedtechniques with respect to potential therapeutic use of genetransfer systems and gene modulation.     

Genetic association between the phospholipase A2 gene and unipolar affective disorder: a multicentre case-control study

The co-segregation in one pedigree of bipolar affective disorder with Darier's disease whose gene is on chromosome 12q23-q24.1, and findings from linkage and association studies with the neighbouring gene of phospholipase A2 (PLA2) indicate that PLA2 may be considered as a candidate gene for affective disorders. All relevant genetic association studies, however, were conducted on bipolar patients. In the present study, the possible association between the PLA2 gene and unipolar affective disorder was examined on 321 unipolar patients and 604 controls (all personally interviewed), recruited from six countries (Belgium, Bulgaria, Croatia, Germany, Greece, and Italy) participating in the European Collaborative Project on Affective Disorders. After controlling for population group and gender, one of the eight alleles of the investigated marker (allele 7) was found to be more frequent among unipolar patients with more than three major depressive episodes than among controls (P<0.01); genotypic association was also observed, under the dominant model of genetic transmission (P<0.02). In addition, presence of allele 7 was correlated with a higher frequency of depressive episodes (P<0.02). These findings suggest that structural variations at the PLA2 gene or the chromosomal region around it may confer susceptibility for unipolar affective disorder.     

Interaction between sympathetic nerve activation and muscle fibre contraction in resistance vessels of hamster retractor muscle

The interaction between skeletal muscle contraction and sympathetic nerve activation (SNA) on blood flow during exercise has remained ambiguous due to indirect estimates of vasomotor control. In the hamster retractor muscle (   n = 54  ), interactions between three levels of SNA (∼3, 6 and 12 Hz) and of contractile activity (2.5, 10 and 20 % duty cycle) were studied in feed arteries (FA) and first- (1A), second- (2A), and third-order (3A) arterioles using intravital microscopy. During functional dilatation with rhythmic muscle contractions, sympathetic vasoconstriction was sustained in FA and 1A but impaired in 2A and 3A (   P < 0.05  ), where vessels 'escaped' from responding to SNA. To account for changes in baseline diameter and blood flow during contractions, vasodilatation was induced passively (2–3 levels) in resting muscles with papaverine or sodium nitroprusside. Compared to functional dilatation, the range of passive dilatation was similar in 3A and progressively greater in 2A, 1A and FA. With passive dilatation, SNA responses were sustained in 2A and increased with baseline diameter in 3A. Blood flow through FA (rest, ∼20 nl s⁻¹) increased ∼5-fold during contractile activity and ∼10-fold during passive dilatation. Absolute flow reductions (nl s⁻¹) with SNA increased during contractile activity and during passive dilatation; relative flow reductions were impaired during functional dilatation (   P < 0.05  ) and remained constant during passive dilatation. Thus, SNA can restrict blood flow to exercising muscle by constricting FA and 1A while dilatation prevails in 2A and 3A. Such concerted interaction will promote oxygen extraction when blood flow is restricted to maintain arterial pressure.