Influence of metastatic site as an additional predictor for response and outcome in advanced colorectal carcinoma

Every year, 31,230 men and women are diagnosed with colorectal carcinoma, and up to 60% of these will ultimately develop advanced disease. However, there is little information to identify which patients are most likely to benefit from palliative chemotherapy. This analysis is unique in evaluating how the site of metastasis influences response and survival. A database of 497 patients treated within randomized clinical trials using 5-Fluorouracil (5FU)-based chemotherapy at the Royal Marsden Hospital was analysed. The potential for site of metastasis as a predictive variable for response to chemotherapy and survival was examined, in addition to other clinical parameters. The presence of liver metastases was a better predictor for overall response than either performance status or number of metastatic sites on presentation. Probability of response was significantly decreased by a raised serum carcinoembryonic antigen (CEA) and presence of peritoneal metastases. In liver metastases, a normal serum albumin was as significant a predictor for response as good performance status. The most important predictor for survival was initial performance status. The number of metastatic sites on presentation had no influence on survival. Site of metastasis can predict for response to 5FU-based chemotherapy and patients should be stratified according to the involved site of metastasis in the future.     

Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice

The regulation of stress-induced vocalisations by central NK(1) receptors was investigated using pharmacological antagonists in guinea-pigs, a species with human-like NK(1) receptors, and transgenic NK1R-/- mice. In guinea-pigs, i.c.v. infusion of the selective substance P agonist GR73632 (0.1 nmol) elicited a pronounced vocalisation response that was blocked enantioselectively by the NK(1) receptor antagonists CP-99,994 and L-733,060 (0.1-10 mg/kg). GR73632-induced vocalisations were also markedly attenuated by the antidepressant drugs imipramine and fluoxetine (30 mg/kg), but not by the benzodiazepine anxiolytic diazepam (3 mg/kg) or the 5-HT(1A) agonist buspirone (10 mg/kg). Similarly, vocalisations in guinea-pig pups separated from their mothers were blocked enantioselectively by the highly brain-penetrant NK(1) receptor antagonists L-733,060 and GR205171 (ID(50) 3 mg/kg), but not by the poorly brain-penetrant compounds LY303870 and CGP49823 (30 mg/kg). Separation-induced vocalisations were also blocked by the anxiolytic drugs diazepam, chlordiazepoxide and buspirone (ID(50) 0.5-1 mg/kg), and by the antidepressant drugs phenelzine, imipramine, fluoxetine and venlafaxine (ID(50) 3-8 mg/kg). In normal mouse pups, GR205171 attenuated neonatal vocalisations when administered at a high dose (30 mg/kg) only, consistent with its lower affinity for the rat than the guinea-pig NK(1) receptor. Ultrasound calls in NK1R-/- mouse pups were markedly reduced compared with those in WT pups, confirming the specific involvement of NK(1) receptors in the regulation of vocalisation. These observations suggest that centrally-acting NK(1) receptor antagonists may have clinical utility in the treatment of a range of anxiety and mood disorders.     

Impact of the fungicide carbendazim in freshwater microcosms. I. Water quality, breakdown of particulate organic matter and responses of macroinvertebrates

Effects of chronic application of the fungicide Derosal(R) (active ingredient carbendazim) were studied in indoor macrophyte-dominated freshwater microcosms. The concentrations (0, 3.3, 33, 100, 330 and 1000 μg/l) were kept at a constant level for 4 weeks. This paper is the first of a series of two, and describes the fate of carbendazim and its effects on water quality parameters, breakdown of POM, and responses of macroinvertebrates. Carbendazim proved very persistent in the water layer. Values for t(12) varied between 6 and 25 weeks, and decreased with the treatment level. Significant effects on water quality parameters (DO, pH, alkalinity, conductivity) could not be demonstrated. After 4 weeks of incubation, the breakdown of Populus leaves was significantly slower at the two highest carbendazim concentrations. The macroinvertebrate community was seriously affected by carbendazim application, with Oligochaeta, Turbellaria, Hirudinea and some Crustacea as the most sensitive groups. The snail Bithynia decreased in numbers, but other gastropods increased in numbers. Safety factors as proposed by the Uniform Principles (European Union) for the risk assessment of pesticides, to be multiplied with toxicity data of the standard test species (Daphnia, fish, algae), appeared to ensure adequate protection of sensitive populations present in the microcosms.     

Modulation of morphine sensitization in the rat by contextual stimuli

Rationale: The repeated administration of addictive drugs, such as amphetamine, cocaine, and morphine, produces a progressive enhancement (sensitization) of their psychomotor activating effects. We have previously shown that administration of amphetamine or cocaine in a distinct test environment promotes more robust psychomotor sensitization than if they are given at home. No information is available, however, on whether this environmental manipulation has a similar effect on sensitization to morphine, a drug that enhances dopamine (DA) release in the striatum indirectly by disinhibiting midbrain DA neurons. Objectives: The main goal of present study was to determine whether exposure to a distinct environmental context facilitates morphine sensitization. Methods: As an index of psychomotor activation, we used rotational behavior in rats with a uni- lateral 6-hydroxydopamine lesion of the mesostriatal DA system. There are inconsistencies in the literature regarding the ability of morphine to elicit rotational behavior. Therefore, in experiment 1 we determined the effect of 2.0, 3.0, 4.0, 6.0, and 8.0 mg/kg, IP, of morphine on rotational behavior. In experiment 2, we studied the effect of five consecutive IV infusions of saline or morphine (2.0 mg/kg) in rats treated either in their home cage or in a distinct and relatively novel test environment. After 5 days of withdrawal, all rats received an IV infusion of 2.0 mg/kg morphine (Morphine challenge). The following day all rats received an IV infusion of saline (Saline challenge). Results: Morphine produced a dose-dependent increase in rotational behavior. Environmental novelty enhanced both the acute psychomotor response to morphine and its ability to induce psychomotor sensitization. Furthermore, a conditioned rotational response was seen only in animals treated in the novel environment. Conclusions: Environmental novelty can facilitate the development of sensitization to the psychomotor activating effects of major addictive drugs, such as amphetamine, cocaine, and morphine. Received: 29 November 1999 / Accepted: 14 March 2000     

Decreased prostaglandin E turnover in infants with essential fatty acid deficiency

Sick low birth weight infants (LBWI) are prone to develop rapid onset of essential fatty acid (EFA) deficiency. EFAs serve as precursors for prostaglandins (PGs). We measured the excretion of the major urinary metabolite of prostaglandins E1 and E2, 7alpha-hydroxy-5,11-diketotetranorprostane-1,16-dionic acid (PGE-M), in three EFA-deficient and in nine thriving neonates. There was no significant difference in PGE-M excretion between the sexes among thriving infants nor did PGE-M excretion appear to be affected by postconceptual age. However, a significant difference between the PGE-M excretion in the group of infants with EFA deficiency before and after treatment is apparent (P less than 0.05). Significant differences in PGE-M excretion were also found between the control group and the EFA-deficient infants. The severity of the EFA deficiency correlates directly with the degree of PGs excretion. The biochemical evidences of EFA deficiency and the decreased levels of PGE-M excretion are rapidly corrected when patients resume a diet containing EFA.     

Joint Recommendations for Reporting Carotid Ultrasound Investigations in the United Kingdom

At present in the United Kingdom a number of different criteria are used to grade disease in carotid ultrasound investigations. One main cause of this has been the difference in the method of grading angiograms used in the NASCET and ECST large carotid surgery trials. It is desirable that all centres reporting carotid ultrasound investigations report to the same standard. This paper presents recommendations for the reporting of ultrasound investigations of the extra cranial arteries produced by a Joint Working Group formed between the Vascular Society of Great Britain and Ireland, and the Society for Vascular Technology of Great Britain and Ireland. The recommended criteria are based on the NASCET method of grading carotid bulb disease. Key recommendations include recording peak systolic velocity (PSV) and end-diastolic velocity (EDV) in both internal and distal common carotid arteries; measuring all velocities at a Doppler angle of 45–60°; the use of internal carotid PSV of >1.25 ms^?1 and >2.3 ms^?1 and a Peak Systolic Velocity Ratio of >2 and >4 to indicate >50% and >70% stenosis respectively; and the use of the St Mary's Ratio to grade >50% stenoses in deciles. General recommendations are also given for the acquisition, interpretation and reporting of the data.     

Neuropsychiatric side-effects of lidocaine: examples from the treatment of headache and a review

Lidocaine has been used in treatment of patients with refractory headache. Personal observations of neuropsychiatric toxicity in these patients led us to review our cases and the literature systematically for lidocaine side-effects, especially neuropsychiatric symptoms. In our series of 20 patients, side-effects were observed in all, the most frequent being neuropsychiatric (75%) and cardiological (50%). When reviewing published series on intravenous lidocaine use, reports of side-effects range from 0 to 100%, with neuropsychiatric symptoms being reported in 1.8–100%. Thirty-six case reports of lidocaine-induced psychiatric symptoms were also analysed. Psychiatric symptoms of toxicity were similar in most patients, despite their differing ages, pathologies, co-therapies and lidocaine dosages. In conclusion, lidocaine neuropsychiatric toxicity has a well-recognized stereotypical clinical presentation that is probably unrecognized in headache series. As lidocaine represents an emerging alternative therapy in headache, particularly in short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, clinicians and patients should be aware of the extent of this problem.     

Vasodilator agents and supracollicular transection fail to inhibit cortical spreading depression in the cat

It remains an open question as to whether cortical spreading depression (CSD) is the pathophysiological correlate of the neurological symptoms in migraine with aura. In the experimental animal, CSD is an electrophysiological phenomenon mainly mediated via NMDA receptors. However, according to case reports in humans, visual aura in migraine can be alleviated by vasodilator substances, such as amyl nitrite and isoprenaline. There is also circumstantial evidence that brainstem nuclei (dorsal raphe nucleus and locus coeruleus) may play a pivotal role in the initiation of aura. In this study, CSD was elicited in alpha-chloralose anesthetized cats by cortical needle stab injury and monitored by means of laser Doppler flowmetry. Topical application of isoprenaline (0.1-1%) and amyl nitrite (0.05%) onto the exposed cortex had no effect on the elicitation or propagation of CSD. Also, after supracollicular transection, subsequent CSDs showed no differences in the speed of propagation and associated flow changes. We conclude from these data that--given CSD probably exists in humans during migraine--spreading neurological deficits during migraine aura are independent of brainstem influence and have a primarily neuronal rather than vascular mechanism of generation.     

Comparative injury rates of uninjured, anterior cruciate ligament-deficient, and reconstructed knees in a skiing population.

To evaluate the risks of skiing after anterior cruciate ligament injury with or without reconstruction, we performed a 3-year study of 5646 skiers employed by a large ski resort. All skiers underwent knee ligament examinations before entering the study. The participants were divided into three groups based on whether they had never had an anterior cruciate ligament injury (N = 4748), were unilaterally deficient of the ligament (N = 138), or had undergone a unilateral reconstruction of the ligament at least 1 year before (N = 274). The rates of knee injuries requiring evaluation by a physician or time off work were calculated. The results of the reconstructed knees were further evaluated to determine whether ligament repair with semitendinosus/gracilis or patellar tendon autograft had a higher injury rate. Compared with knees with intact anterior cruciate ligaments, ligament-deficient knees had a 6.2-times higher rate of injuries, and knees in which the ligament had been reconstructed had a 3.1-times higher rate. The differences between each of the three groups were significant. Injuries to ligament-intact knees were less severe, with 13% requiring surgery, while 39% of the injuries in the ligament-deficient and 41% of the injuries in the reconstructed-ligament knees required surgery. The rates of injury for the graft types were not significantly different, but skiers with a semitendinosus/gracilis tendon autograft were significantly more likely to rupture their graft than skiers with a patellar tendon autograft.