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.     

Excellent results of a femoral press-fit stem cemented with a thin mantle: 116 hips followed for 11–18 years

We report the outcome of a femoral stem designed for press-fit insertion and cemented with a thin mantle. During the years 1986–1992 we performed 346 primary total hip replacements in 305 patients. Their mean age at the time of the surgery was 75 (range, 52–91 years). During the follow-up, 206 patients had died (227 hips) and 3 were lost. This left us with 96 patients (116 hips), who were followed for a mean of 13 years (range, 11–18 years). Stem survivorship according to Kaplan–Meier analysis indicated a total survival of 0.982 (confidence intervals, 0.952–1). The mechanical survival rate was 0.985 (confidence intervals, 0.955–1) at 17 years with one patient at risk. Fifty-nine (70%) of the surviving patients were very satisfied with the operated hip, 22 (26%) were satisfied, 2 (2.5%) were content, and 1 (1.5%) was dissatisfied. Then, the press-fit stem allowing minimal cement has a 17-year survival rate of 0.98.     

Effects of nail rigidity on fracture healing

The present study was undertaken to assess the effects of the rigidity of nails on the healing of fractures as evaluated by mechanical strength and rate of bone mineralisation. Ten rats supplied biomechanical data at the start of the experiment and another 100 rats were randomly assigned to 5 groups. In 20 rats no intervention was performed, and they served as a reference group of normal values. Thus, 80 rats underwent a standardised partial osteotomy in the left femur diaphysis prior to manual fracture, reaming and intramedullary nailing. One group received rigid steel nails (group 1) and another, cannulated steel nails (group 2). Group 3 received semi-rigid titanium nails and group 4, soft polyethylene nails. Ten rats in each group were evaluated at 6 and 12 weeks after fracture, and radiographs and callus diameter measurements were performed. Dual-energy X-ray absorptiometry (DEXA) of the bones was performed, and the degree of mineralisation in the callus segment, distal diaphysis and total femur was calculated by the scanner. Subsequently, the bones were tested mechanically by a three-point bending test in a Mini Bionix (MTS) testing system. Radiographs revealed clearly visible fractures at 6 weeks in the intervention groups. At 12 weeks there were no signs of bridging callus in group 4, while the other groups presented scarcely visible osteotomies. The callus area in group 4 was significantly larger at both 6 and 12 weeks than in groups 1–3. In these groups there was a significant decrease in callus area between 6 and 12 weeks. Both maximum bending load, bending rigidity and fracture energy increased significantly in groups 1–3 between 6 and 12 weeks, while bending load and fracture energy increased in group 4. At 6 weeks no significant differences were detected between groups 1–3 in mechanical strength. Group 4 had a significantly reduced maximum bending load and fracture energy at 6 and 12 weeks as well as bending rigidity at 12 weeks. At 12 weeks group 3 had a significantly increased maximum bending load and fracture energy compared with groups 1 and 2. Bone mineral count (BMC) in the callus region in group 4 was significantly reduced at both 6 and 12 weeks. BMC in the callus showed no significant differences between groups 1–3, either at 6 or at 12 weeks. BMC in the distal diaphysis was significantly reduced in groups 1 and 4 compared with group 2 at 12 weeks. Bone mineral density (BMD) in the callus region revealed no significant differences between groups 1–3 at 6 weeks, while at 12 weeks BMD was higher in group 3 than in group 1. BMD in the callus region and total femur in group 4 was significantly reduced at 6 weeks. This study demonstrates that diaphyseal fractures treated with titanium nails with a bending rigidity similar to the intact femur have a higher maximum bending load and fracture energy at 12 weeks than both rigidly or softly nailed fractures. BMD in the callus region was also highest after titanium nailing at 12 weeks. BMD in the distal diaphysis and total femur indicates that the degree of stiffness of the nails have little influence on total bone mineralisation at 12 weeks.     

Brace with a lateral pad for patellar pain. 2-year follow-up of 25 patients

A patellar brace with a lateral pad was used in 25 patients with unilateral retropatellar pain syndrome. The patients were told to use the brace in activities that loaded the patella, and they were followed for 1 to 2 years. At follow-up, 8 patients were improved, while the symptoms were unchanged or worse in 17. The level of activity was increased in 4 patients, reduced in 3, and unchanged in the others. It is concluded that treatment with a patellar brace with a lateral pad is not likely to succeed in the majority of patients with retropatellar pain syndrome.     

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.     

Effects of Clodronate on Cortical and Trabecular Bone in Ovariectomized Rats on a Low Calcium Diet

The aim of this study was to evaluate the contribution of a low calcium diet to the cortical and trabecular osteoporosis seen in ovariectomized rats after 7 weeks on a low calcium diet and to investigate the effects of the bisphosphonate clodronate on this development of osteoporosis. Thirty-six mature, female Wistar rats were randomized into four groups: Ovx−B (bisphosphonate) and Ovx−C (control) were ovariectomized, and Sham−Ca (low calcium) and Sham+Ca (normal calcium) were sham operated. The first three groups were fed a low calcium diet (0.01%) and Sham+Ca normal rat chow (Ca 1.1%). The Ovx−B received 10 mg/kg s.c. clodronate daily for nine weeks, and Ovx−C, Sham−Ca, and Sham+Ca received the same volumes of saline. Bone mineral turnover measured as ⁸⁵Sr-uptake was increased in all low calcium groups compared to Sham+Ca. The Sham+Ca femora had higher dry weight and ash weight than the other groups, and Ovx−C had higher dry weight compared with Ovx−B and Sham−Ca. Calcium content was lower in both Ovx groups compared to both Sham groups. Magnesium was lower in all groups compared to Sham+Ca and higher in Ovx−B compared with Ovx−C. In the femoral shaft, Sham+Ca had significantly higher ultimate bending moment, energy absorption, and deflection compared to the other three groups. Ultimate bending moment was higher in Sham−Ca than in Ovx−C. Stiffness was increased in both Sham+Ca and Ovx−B compared to Ovx−C. The maximum stress in the femoral midshaft was higher in Sham+Ca than in the other groups, and higher in Ovx−B than in Ovx−C. Histomorphometry showed increased medullary area in all low calcium groups compared to Sham+Ca and larger cortical area in Sham+Ca and Ovx−B compared to Ovx−C. Compared to Sham+Ca the trabecular bone volume was decreased to 30% in Sham−Ca and to 9% in Ovx−C, but was unchanged in Ovx−B. The low calcium diet generally increased bone mineral turnover and reduced the tibial bone volume. Femoral changes led to a reduction of cortical fracture strength and maximal stress. Ovariectomy in addition to a low calcium diet reduced femoral strength even more. Daily injections of clodronate to ovariectomized rats on a low calcium diet increased femoral shaft stiffness and maximum stress, and clodronate preserved both trabecular and cortical tibial bone volume completely. Received: 11 June 1996 / Accepted: 5 March 1997     

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.