Radioimmunodetection of Ovarian Cancer

Radioimmunoscintigraphy (RIS) is a potentially valuable method for the detection of primary, secondary and recurrent malignant tumours. Antigens that have been used for monitoring as well as for RIS of ovarian carcinomas include CA 125, PLAP, HMFG, and CA 19-9. Between 70 and 100% of the tumours have been detected at RIS when these antigens have been used. Conventional methods, e.g., computerized tomography (CT) and ultrasonography (US), demonstrate similar or lower detection rate than RIS for tumour diagnosis. RIS gives additional information to conventional radiological methods (CT and US) for the detection of occult ovarian carcinomas. A review of earlier investigations is given and our own recent results using PLAP as a target antigen are presented. The future potential of the technology is discussed.     

Topiramate augments the antipsychotic-like effect and cortical dopamine output of raclopride

Recent clinical studies have shown that the anticonvulsant drug topiramate may improve negative symptoms in schizophrenia when added to a stable regimen of neuroleptic medication. It has also been shown that addition of topiramate to neuroleptics might be beneficial in treatment-resistant schizophrenia. Clinically effective doses of antipsychotic drugs (APDs) have been found to suppress conditioned avoidance response behavior (CAR), a preclinical test of antipsychotic activity with high predictive validity, in rats. Therefore, we investigated the putative antipsychotic-like activity of topiramate when added to the selective dopamine (DA) D₂ receptor antagonist raclopride, using the CAR model in the rat. Extrapyramidal side effect liability of the drug combination was evaluated in parallel by means of the catalepsy test. We also examined the effect of this drug treatment on DA release in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis in freely moving animals. Topiramate (40 mg/kg), while ineffective when given alone, significantly augmented the antipsychotic-like effect of raclopride (0.075 mg/kg) on CAR without any concomitant catalepsy. Addition of topiramate to rats treated with raclopride generated a large increase in DA output in the mPFC, whereas no additional effect on the raclopride-induced DA release in the NAC was obtained. These data support the adjunctive use of topiramate in schizophrenia to ameliorate negative symptoms and suggest that this treatment may increase the efficacy, but not the extrapyramidal side effect liability, of the APDs used.     

Active immunisation against nicotine blocks the reward facilitating effects of nicotine and partially prevents nicotine withdrawal in the rat as measured by dopamine output in the nucleus accumbens, brain reward thresholds and somatic signs

We recently showed that active immunisation with the nicotine immunoconjugate IP18–KLH reduces the nicotine-induced increase in dopamine (DA) output in the nucleus accumbens (NAC) and prevents reinstatement of nicotine-seeking behaviour in rats. These effects are mediated by altered distribution of nicotine, resulting in reduced amounts of nicotine reaching the brain, thereby interfering with the rewarding properties of the drug. The present study was designed to explore the effect of immunisation against nicotine on mecamylamine-precipitated nicotine withdrawal as assessed by the reduction in DA output in the NAC in rats. Measuring brain reward thresholds and somatic signs of nicotine withdrawal, the effects of immunisation were also tested during chronic nicotine treatment and after its withdrawal. Finally, we examined the effect of immunisation on challenge injections of nicotine on brain reward thresholds after the increases in somatic signs and reward thresholds associated with nicotine withdrawal had dissipated. The results show that immunisation with IP18–KLH prevented the decrease in DA output in the NAC associated with mecamylamine-precipitated nicotine withdrawal. Moreover, immunisation against nicotine did not precipitate a withdrawal syndrome, as measured by brain reward thresholds and somatic signs, in rats chronically exposed to nicotine. Furthermore, the withdrawal syndrome elicited after cessation of chronic nicotine administration was attenuated in immunised rats compared to that of mock-immunised rats. Finally, the lowering in reward thresholds after nicotine challenge injections was attenuated in both naïve and previously nicotine-exposed immunised rats. In conclusion, the present results show that immunisation with IP18–KLH did not precipitate nicotine withdrawal in rats. Thus, immunisation with IP18–KLH may not elicit nicotine withdrawal in smokers either. Furthermore, since the withdrawal syndrome in rats was attenuated by immunisation, the nicotine withdrawal in smokers should not be worsened but may even be ameliorated during a quit attempt.     

Tumour vascular endothelial growth factor (VEGF) mRNA in relation to serum VEGF protein levels and tumour progression in human renal cell carcinoma

Angiogenesis is gaining interest because of its importance in tumour growth and metastasis. Renal cell carcinoma (RCC) is known to be a well-vascularized tumour. The aim of this study was to evaluate the expression of VEGF mRNA and receptor flt-1 mRNA (VEGF R1) in a clinical material of RCCs compared with clinicopathological variables and serum VEGF levels. Total RNA was extracted from snap-frozen tumour tissue obtained from 61 patients. Expression of mRNA for VEGF₁₂₁, VEGF₁₆₅ and flt-1 were analysed using quantitative RT-PCR. Relative VEGF mRNA levels, corrected for corresponding cyclophilin value, were related to stage, grade, RCC type and survival time. Serum VEGF₁₆₅ protein was analysed using a quantitative ELISA. Papillary RCC had significantly lower VEGF₁₂₁ and flt-1 mRNA levels compared with conventional RCC (p=0.001). VEGF₁₂₁ mRNA levels were significantly lower in locally advanced tumours in relation to tumours limited to the kidney and those with metastatic disease (p=0.047 and p=0.036). This statistical difference disappeared when only conventional RCCs were evaluated. No association was found between VEGF mRNA levels and nuclear grade. Patients with lower VEGF₁₂₁ mRNA levels had significantly longer survival time compared with those with higher levels (when adjusted to stage, p=0.0097, log rank test). There was an inverse relation between VEGF₁₆₅ mRNA and serum VEGF₁₆₅ levels. The trend to lower VEGF₁₂₁ mRNA levels in locally advanced RCC indicate that angiogenic activity and degradation might be up-regulated in tumours with a high ability to invade. The association with tumour progression shows that VEGF is a promising angiogenic factor especially important in conventional RCCs. VEGF expression might possibly be of help to identify RCCs susceptible for anti-angiogenic therapies.     

Elevated neurofilament levels in neurological diseases

Neurofilaments, a major cytoskeletal constituent of neuronal cells, can be released into the cerebrospinal fluid during several neurodegenerative diseases. By means of a new sensitive ELISA capable of measuring 60 ng/l of neurofilament light, significant elevations were observed for different neurological disorders. Cerebral infarction presented levels of 19800+/-9100 ng/l, amyothropic lateral sclerosis 3600+/-1200 ng/l, 'relapsing-remitting' MS 2500+/-1500 ng/l, extrapyramidal symptoms 1100+/-300 ng/l, late onset AD 300+/-100 ng/l and vascular dementia 1400+/-800 ng/l. In patients with no signs of neurological diseases the upper normal level and cut-off values was determined to be below 100 ng/l. NF-L determinations will be a valuable complement in identifying neuronal degradation and can be used clinically for diagnostic and monitoring purposes.     

Alpha-adrenoceptor modulation hypothesis of antipsychotic atypicality

Although all currently used antipsychotic drugs act as dopamine (DA) D2 receptor antagonists, clozapine, the prototype for atypical antipsychotics, shows superior efficacy, especially regarding negative and cognitive symptoms, in spite of a significantly reduced central D2 receptor occupancy compared with typical (conventional) antipsychotic drugs. Clozapine, as well as several other atypicals, displays significant affinities also for several other neurotransmitter receptors, including other dopaminergic receptors, alpha-adrenergic receptors and different serotonergic and cholinergic receptors, which in several ways may contribute to the clinical effectiveness of the drugs. Preclinical and clinical results suggest a dysregulated mesocorticolimbic DA system in schizophrenia, with an impaired prefrontal DA projection, which may relate to negative and cognitive symptoms, concomitant with an overactive or overreactive striatal DA projection, with bearing on psychotic (positive) symptomatology. Available data suggest that blockage of alpha1-adrenoceptors by antipsychotics may contribute to suppress positive symptoms, especially in acute schizophrenia, whereas alpha2-adrenoceptor blockage, a prominent effect of clozapine and, to some extent, risperidone but not other antipsychotics, may rather be involved in relief of negative and cognitive symptoms. Whereas alpha1-adrenoceptor blockage may act by suppressing, at the presynaptic level, striatal hyperdopaminergia, alpha2-adrenoceptor blockage may act by augmenting and improving prefrontal dopaminergic functioning. Thus, the prominent alpha1- and alpha2-adrenoceptor blocking effects of clozapine may generally serve to stabilize dysregulated central dopaminergic systems in schizophrenia, allowing for improved efficacy in spite of a reduced central D2 receptor occupancy compared with typical antipsychotic drugs.     

Hypoxia-inducible factor 1alpha expression in renal cell carcinoma analyzed by tissue microarray

OBJECTIVES: Angiogenesis is important for tumour progression and metastatic spread. Hypoxia-inducible factor 1alpha (HIF-1alpha) is a major factor regulating a number of other angiogenic factors. Renal cell carcinoma (RCC) is a malignancy with a variable clinical course, partly attributable to specific genetic alterations of the different RCC types. We therefore analysed HIF-1alpha expression using immunohistochemistry and related the results to RCC type and clinicopathologic variables. MATERIAL AND METHODS: We semiquantitatively analysed HIF-1alpha expression using immunohistological staining of a prepared tissue microarray. There were 216 patients including 176 conventional, 26 papillary, and 14 chromophobe RCCs. RESULTS: The HIF-1alpha staining was found mainly in the cytoplasm. The tumours were subdivided into HIF-1alpha(LOW) and HIF-1alpha(HIGH) on the basis of staining intensity. HIF-1alpha expression between the RCC types did not differ. Patients with conventional RCC showed a trend (p=0.055) towards a prolonged survival for those with HIF-1alpha(HIGH)-staining versus HIF-1alpha(LOW)-staining tumors. In conventional RCC there were significant differences in HIF-1alpha expression in relation to TNM stage, nuclear grade, and vein invasion. In patients with papillary RCC, difference in HIF-1alpha expression was observed only for nuclear grade. CONCLUSIONS: We studied HIF-1alpha expression in RCC using tissue microarray. In patients with conventional RCC, HIF-1alpha levels were significantly lower in locally aggressive tumors versus localized tumors, and patients with high HIF-1alpha levels tended to have a better prognosis. There seems to be a diverging regulation of angiogenesis between the different RCC types. Further studies of HIF and angiogenesis in RCC are encouraged.     

Risk of parathyroid adenomas in patients with thyrotoxicosis exposed to radioactive iodine

External ionizing radiation is a risk factor for primary hyperparathyroidism. Whether exposure to radioactive iodine contributes to the risk of primary hyperparathyroidism is unknown. Patients with thyrotoxicosis are often treated with radioactive iodine and its accumulation in the thyroid gland exposes the adjacent parathyroid glands to radioactivity. Six thousand and eighty two patients with thyrotoxicosis (ICD-9 = 242) were identified from medical records. In a randomly selected subcohort we assessed the frequency of treatment with radioactive iodine to be 86%. The number of patient-years at risk was 77,118. Patients with parathyroid adenomas (ICD-9 = 195.1) were recruited from the Swedish Cancer Registry. Eleven patients with parathyroid adenomas following the diagnosis of thyrotoxicosis were identified. The standard incidence ratio (SIR) compared to the reference population of approximately 900,000 was 1.14 (95% CI 0.57-2.03). The median age at exposure was 59 years and the latency period between diagnosis of thyrotoxicosis and parathyroid adenoma was 7.4 years (range <1-19 years). This study does not indicate that patients with thyrotoxicosis treated with radioactive iodine in adult age have increased risk of developing parathyroid adenoma.     

Emerging Aspects of the Adrenergic Nervous Systems

The present paper reviews some recent experiments with relevance to the functional significance of brain noradrenergic systems with bearing on three clinically relevant topics: 1. The withdrawal and abstinence reactions after the antihypertensive agent clonidine as well as after opiates. 2. The mental reactions associated with alterations in blood volume and acid-base balance. 3. The central actions and side-effects of β-adrenoceptor blocking agents. The available evidence indicates that central NA neurons may serve a function within the CNS analogous to that of the peripheral sympathetic nerves, i.e. to alert and alarm the individual to significant events in the external and internal environment. Thus, the largest brain NA system, which emanates from locus coeruleus and innervates vast regions of the neuroaxis, is largely activated in the same situations and by the same mechanisms (e.g. blood-volume and chemoreceptors) as the sympathetic system, and may provide part of the central machinery for the anxiety reaction associated with hypercapnia as well as the withdrawal reactions after clonidine or morphine. Some, but not all centrally active β-adrenoreceptor blocking agents were found to affect the activity of brain NA systems. This result suggests that there may be significant differences with respect to the clinical, central side effects of these drugs.     

Serum levels of placental alkaline phosphatase in high-risk pregnancies

A recently developed radioimmunoassay (RIA) for placental alkaline phosphatase (paf) was used to estimate the maternal serum levels of the enzyme in 51 women with various complications of pregnancy. The results were compared with a reference group of 242 women with apparently normal pregnancies. Women with intrauterine growth retardation (IUGR) or severe or mild preeclampsia had significantly low weight of the fetoplacental unit. Simultaneous determinations of PAF in maternal serum and the urinary total estrogen/24 hr gave a clear differentiation of the IUGR group from the other pregnancies at risk. All PAF values from risk pregnancies were below the mean values of normal pregnancy.