55Cobalt (Co) as a PET-tracer in stroke, compared with blood flow, oxygen metabolism, blood volume and gadolinium-MRI

Axonal degeneration plays an important role in the accumulation of disability in patients with multiple sclerosis (MS). Pathological studies have demonstrated axonal damage, particularly in areas of acute inflammation and demyelination, and in chronic lesions. Axonal loss and its progression, which is associated with neurological disability, has also been demonstrated by magnetic resonance imaging (MRI) studies. The mechanisms of axonal loss are uncertain, but may involve axonal degeneration secondary to demyelination, or damage to the axonal cytoskeleton. Inflammatory mediators, including cytokines and proteolytic enzymes may contribute to axonal damage, as may nitric oxide. Axonal destruction may also be due to immune attack directed at axonal components. The realisation that axonal degeneration is a fundamental component of MS that may occur early in the disease course should alter the approach to management and open avenues to a more targeted immunotherapy aimed at reducing the progression of disability.     

Multiple regulatory elements result in regional specificity in circadian rhythms of neuropeptide expression in mouse SCN

It is well established that the mammalian circadian system consists of pacemaker cells in the suprachiasmatic nuclei (SCN). The mouse has become increasingly important in understanding the circadian timing system, due to the availability of mutant animals with abnormal circadian rhythms. In the present paper, we describe the organization of the mouse SCN, comparing the wild type and Clock mutant animal, with a special focus on those peptides bearing an upstream E-box element (vasopressin, vasoactive intestinal peptide, cholecystokinin and substance P). To this end, we describe the distribution of the foregoing SCN peptidergic cell types as well as gastrin-related peptide, calretinin, calbindin, somatostatin, neurotensin and retinal input to the SCN (determined by both tract tracing and fos-immunoreactivity in response to a light pulse). The Clock mutant mouse has decreased expression of vasopressin mRNA and protein in the SCN, with normal patterns of expression elsewhere in the brain. No other differences were detected between the Clock mutant and the wild type mouse. The results are consistent with the hypothesis that there are multiple regulatory elements of clock-controlled genes in the SCN.     

The in vitro effects of instrumentation on multilevel cervical strut-graft mechanics

STUDY DESIGN: Biomechanical study using a programmable testing apparatus that replicated physiologic flexion-extension cervical spine motion, and loading mechanics. OBJECTIVES: To determine the influence of anterior, posterior, or combined plating on multilevel cervical strut-graft mechanics in vitro. SUMMARY OF BACKGROUND DATA: The addition of instrumentation does not prevent construct failure in multilevel (more than two levels) cervical corpectomy. METHODS: Six fresh human cadaveric cervical spines (C2-T1) were tested in six sequential conditions that included harvested (H), C4-6 corpectomy, strut grafted, strut grafted with an anterior cervical plate (SGAP), strut grafted with posterior plates (SGPP), and strut grafted with combined anterior and posterior plates (SGAPP). A customized force-sensing strut graft (FSSG) was used to measure axial compression-tension, flexion-extension and lateral bending moments, and axial torsion. Parameters of stiffness, segmental vertebral motion, and strut-graft loads were compared, to determine differences among the spine conditions. RESULTS: Flexion of the strut-grafted spine loaded the FSSG, and extension motion unloaded the FSSG. With the anterior plate, flexion of the SGAP spine significantly unloaded the FSSG; extension loaded the FSSG more than flexion of the unplated spine (P = 0.03). The opposite occurred with the posterior plates (SGPP), where flexion of the spine significantly loaded the FSSG (more than the strut grafted spine) and extension unloaded the FSSG (P < 0.03). The combined construct (SGAPP) counteracted the tension band effect of the individual plates and demonstrated significantly less overall FSSG load change than either plate alone (P = 0.03). CONCLUSIONS: Multilevel cervical instrumentation effectively increases stiffness after corpectomy. However, anterior or posterior plating alone excessively loads the graft with small degrees of motion, which may promote pistoning and failure of multilevel constructs.     

Recording of swallowing events using electromyography as a non-invasive measurement of salivation

The present study examined whether the measurement of swallowing activity by electromyography (EMG) provides a sensitive and valid method for the assessment of the amount of saliva secreted. Thirteen subjects tasted lemon juice and water, and smelled lasagna and hay, while the amount of saliva, measured with the aid of cotton dental rolls, was compared with the number of peaks in the EMG activity of the musculus digastricus. Swallowing indeed differentiated between the stimuli and the correlation between the number of swallows and the amount of saliva was significant. The present data suggest that monitoring the swallowing movement using EMG might be a sensitive, valid and reliable method for the measurement of salivary flow. The use is recommended for the measurement of salivation when a simple and non-invasive method is needed.     

An experimental test of the relationship between self-esteem and concern about body shape and weight in restrained eaters

OBJECTIVE: Although self-esteem and overconcern with body shape and weight are considered to be closely connected in bulimia nervosa, little empirical research has been done to investigate the alleged link. METHOD: In this study, we examined experimentally whether overconcern with body shape and weight was connected with self-esteem in an analogue sample of high restrained eaters by means of a subliminal lexical decision task. RESULTS: It could indeed be demonstrated that low self-esteem and overconcern with body shape and weight are associated in high restrained eaters: after priming low self-esteem, the accessibility of subliminally presented body shape and weight stimuli was increased. The effect was not found with a supraliminal lexical decision task. DISCUSSION: Apparently, the automatic, nonconscious processing of body shape and weight words was influenced in high restrained eaters with a low state self-esteem, whereas the strategic, conscious processing was not. As soon as the body shape and weight stimuli were processed consciously, the initial increased accessibility was countered and the effect disappeared.     

ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1

The present study was performed to investigate the ability of the multidrug resistance protein (MRPI) to transport different cationic substrates in comparison with MDR1-P-glycoprotein (MDR1). Transport studies were performed with isolated membrane vesicles from in vitro selected multidrug resistant cell lines overexpressing MDR1 (A2780AD) or MRP1 (GLC4/Adr) and a MRP1-transfected cell line (S1(MRP)). As substrates we used 3H-labelled derivatives of the hydrophilic monoquaternary cation N-(4',4'-azo-in-pentyl)-21-deoxy-ajmalinium (APDA), the basic drug vincristine and the more hydrophobic basic drug daunorubicin. All three are known MDR1-substrates. MRP1 did not mediate transport of these substrates per se. In the presence of reduced glutathione (GSH), there was an ATP-dependent uptake of vincristine and daunorubicin, but not of APDA, into GLC4/Adr and S1(MRP) membrane vesicles which could be inhibited by the MRP1-inhibitor MK571. ATP- and GSH-dependent transport of daunorubicin and vincristine into GLC4/Adr membrane vesicles was inhibited by the MRP1-specific monoclonal antibody QCRL-3. MRP1-mediated daunorubicin transport rates were dependent on the concentration of GSH and were maximal at concentrations > or = 10 mM. The apparent KM value for GSH was 2.7 mM. Transport of daunorubicin in the presence of 10 mM GSH was inhibited by MK571 with an IC50 of 0.4 microM. In conclusion, these results demonstrate that MRP1 transports vincristine and daunorubicin in an ATP- and GSH-dependent manner. APDA is not a substrate for MRP1.     

Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist.

Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.     

Adjuvant immunotherapy with BCG in squamous-cell bronchial carcinoma. Immune-reactivity in relation to immunostimulation (preliminary results in a controlled trial).

Jansen, H M, The, T H, de Gast, G C, Esselink, M T, van der Wal, A M, and Orie, N G M (1978).Thorax, 33, 429-438. Adjuvant immunotherapy with BCG in squamous-cell bronchial carcinoma. Immune-reactivity in relation to immunostimulation (preliminary results in a controlled trial). Twenty-nine patients with, at operation, evidence of locally advanced primary squamous-cell bronchial carcinoma (stage II, UICC, Geneva, 1974) had lung resection to remove all the visible tumour. Postoperatively a randomly chosen group of 16 patients received adjuvant BCG immunostimulation by scarifications, while the control group received no adjuvant treatment. Follow-up studies were done from three to 23 months. Immune-reactivity in vivo with PPD and DNCB skin tests, and in vitro with E-rosetting tests and lymphocyte transformation tests with PHA, Con A, diphtheria toxoid, and PPD was monitored in 10 treated and in seven untreated patients. Recurrence rates decreased appreciably in the BCG-stimulated group after a six to 23 months'' follow-up (p<0·005). A pronounced increase in both in-vivo and in-vitro immune-reactivity went in parallel with a more favourable clinical outcome in the BCG-treated group. In these cases there was a significant increase in skin reactivity to PPD three months after surgery (p<0·025) and a statistically significant rise in lymphocyte reactivity to Con A (p<0·05), diphtheria toxoid (p<0·01), and PPD (p<0·05) but not to PHA 12 months after surgery. DNCB skin reactivity increased as well in the BCG-treated group, but the number of individuals was too small for statistical evaluation. Increase in immune responsiveness did not occur in the control group and appeared to be independent of the initial immune state of the patients. No differences were found in the numbers of E-rosetting lymphocytes in relation to immunotherapy. It is concluded that adjuvant BCG immunotherapy used in patients with minimal residual bronchial carcinoma improves the prognosis and a favourable clinical outcome is mirrored by an increase in cellular immune reactivity.     

Chronic infusion of clonidine does not alleviate spontaneous morphine withdrawal symptoms in rats

Opiate withdrawal is associated with behavioural symptoms and a sympathetic hyperactivity, the latter being sensitive to clonidine. The central question is whether behavioural symptoms would be also sensitive to clonidine. A rat model was used in which the locomotor activity was measured 24 h a day during the morphine withdrawal phase. Spontaneous withdrawal of morphine reduced strongly the high nocturnal locomotor activity, concomitently decreasing food intake and body weight. Chronic infusion of clonidine (30–120 µg/kg/day) using osmotic minipumps had no effect on the withdrawal symptoms. Higher dosages (250–1000 µg/kg/day) potentiated rather than alleviated the withdrawal symptoms, suggesting an ₁-adrenergic effect of clonidine rather than an ₂-action. Therefore, we studied the action of a more specific ₂-agonist UK-14.304. UK-14.304 was less potent than clonidine in naive animals. It slightly alleviates the decrease of nocturnal activity during spontaneous morphine withdrawal. Furthermore, we have tested whether the effects of high dosages of clonidine could be altered by a specific ₁-antagonist doxazosine. Doxazosine reduced only slightly the potentiation in the decrease in food intake by clonidine during morphine withdrawal. For the other symptoms no interaction between doxazosine and clonidine was found. The data suggest that the use of clonidine in the detoxification of opiate dependent people is based on the suppression of the sympathetic hyperactivity rather than on symptoms with a more behavioural character.     

Activation of plasma systems and blood cells by endotoxin in rabbits

Endotoxin plays an important role in the pathogenesis of septicaemia by activation of cellular and plasmatic systems. This study was performed to investigate the effects of infusion of endotoxin in rabbits by measuring the activation of cellular and plasma systems. Endotoxin was infused at a rate of 1 mg/kg body wt for 10 min, which caused death of all rabbits within 72 h. Endotoxin induced early leukopenia and thrombopenia, increased plasma levels of-glucuronidase and leukotriene B₄ (LTB₄), and decreased complement total hemolytic activity (CH₅₀) and tissue plasminogen activator (t-PA) activity. These observations correlate with the cellular and plasma changes that have been documented in severely ill endotoxemic patients. Therefore, we conclude that this endotoxin model in rabbits is a valuable tool for investigation of pathophysiology and treatment of endotoxic shock.