Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors

PURPOSE: To evaluate the therapeutic effect of iodine-131-labeled metaiodobenzylguanidine (131I-MIBG) and unlabeled MIBG in patients with carcinoid tumor. MATERIALS AND METHODS: A therapeutic dose of 7.4 GBq (200 mCi) 131I-MIBG infused over 4 hours was administered to 30 patients with either carcinoid syndrome (n = 20) or tumor symptoms such as pain and fever due to carcinoid tumor (n = 10). In general, two courses were given, 6 weeks apart. Due to radioactivity, patients had to be isolated for 5 to 7 days. Subsequently, we studied the effect of unlabeled MIBG based on the possible pharmaceutic activity of MIBG and to avoid the isolation procedure. A doseescalation study of 8.5, 17, and 34 mg/m2 MIBG infused over 4 hours at 4-week intervals was performed in 20 patients with carcinoid syndrome who were not suitable for treatment with the radioactive compound. RESULTS: Following 131I-MIBG treatment, symptomatic responses were observed in 60% of patients (median duration, 8 months; maximum, 2 years). Side effects were mild and rapidly reversible in 16 patients, and were related to the isolation procedure in seven of these patients. Unlabeled MIBG resulted in symptomatic improvement in 60% of patients (median duration, 4.5 months). Side effects, which included changes in blood pressure, were mild and transient. Symptomatic responses were not accompanied by biochemical responses. CONCLUSION: Both MIBG treatment regimens were equally effective in the palliation of symptoms, but duration of response tended to be much longer with the radioactive compound. However, the unlabeled compound provided a simpler treatment, eg, in elderly patients and those in poor condition, without the need for isolation.     

Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons

Activation of courtship behavior in male red-sided garter snakes is independent of androgens. Only exposure to extended periods of low temperature with subsequent warming stimulates courtship in males. The pineal gland is thought to transduce temperature as well as photoperiodic information in reptiles. Therefore, we explored the relationship of the pineal and melatonin to sexual behavior in this species. Pinealectomy of male garter snakes disrupted sexual behavior upon emergence from a 17-week period of low temperature in approximately 60% of treated individuals in each of the 3 years of study. However, 40% of the males were unaffected by the pinealectomy, engaging in vigorous courtship. Administration of exogenous, chronic melatonin did not significantly modulate the effect of pinealectomy. Upon pinealectomy in the autumn (before hibernation), plasma levels of melatonin fell. However, upon emergence from hibernation, melatonin levels in pinealectomized (PINX) and sham-treated (SHAM) animals were equivalent, indicating extrapineal source(s) of melatonin. However, PINX males did not exhibit a diel cycle in melatonin levels upon emergence. Instead, melatonin remained elevated through the subsequent 24-hr period. SHAMs did exhibit a diel cycle. Ten days after emergence, PINX animals either had a disrupted/abnormal melatonin cycle and were non-courters or had a cycle similar to SHAM males and courted. Therefore, a normal diel cycle of melatonin appeared necessary for the proper expression of courtship behavior. These results suggest that the pineal in snakes 1) is part of a complex, multi-oscillator system as it is in birds and lizards and 2) may play a role in maintaining polymorphism in timing of reproductive behavior.     

The intradermal effects of the H3 receptor agonist R alpha methylhistamine in human skin

We have investigated the possible existence of the H3 histamine receptor in human skin with the highly selective ligands R alpha methylhistamine (RAMHA) (H3 agonist) and thioperamide (H3 antagonist). We compared the intradermal effects of RAMHA with histamine, and studied their potential modulation by the H1 antagonist terfenadine, and H2 antagonist cimetidine. The effects of RAMHA and thioperamide on codeine phosphate-, substance P- and histamine-induced weal and flare responses were also studied. RAMHA produced dose-related weal and flare responses that were approximately 10- and fivefold less, respectively, than responses to histamine. Flare responses to RAMHA were significantly inhibited by oral terfenadine (P < 0.05). Weal and flare responses to histamine after oral cimetidine showed much intersubject variation, and cimetidine did not significantly alter either RAMHA- or histamine-induced weal and flare responses. Codeine phosphate-, substance P- and histamine-induced responses were not significantly affected by concurrent administration of RAMHA. Thioperamide was not found to influence codeine phosphate-, substance P-, RAMHA- or histamine-induced effects. RAMHA induces vascular (weal and flare) responses in human skin, and these responses are partially inhibited by terfenadine. There is a trend for RAMHA to have an additive effect to the weal induced by substance P and histamine, although our results largely do not reach statistical significance. Thioperamide does not affect the vascular responses to RAMHA, codeine phosphate, histamine or substance P. We cannot conclude that the effects of RAMHA are induced by H3 receptors on cutaneous endothelial or mast cells.     

Situation models in language comprehension and memory

This article reviews research on the use of situation models in language comprehension and memory retrieval over the past 15 years. Situation models are integrated mental representations of a described state of affairs. Significant progress has been made in the scientific understanding of how situation models are involved in language comprehension and memory retrieval. Much of this research focuses on establishing the existence of situation models, often by using tasks that assess one dimension of a situation model. However, the authors argue that the time has now come for researchers to begin to take the multidimensionality of situation models seriously. The authors offer a theoretical framework and some methodological observations that may help researchers to tackle this issue.     

Principles of urodynamics pressure measurement and its implication to female continence function

Urodynamic pressure measurements using catheters have been widely used among clinicians. More often objective interpretation of urodynamic pressure measurements requires fundamental understanding of pressure measurement techniques due to many measurement artifacts. In this study we developed a simplified compound thick-walled cylinder model to investigate the mechanical nature of urodynamic pressure measurement as well as pressure transmission. Efficacy of collagen implantation was also explored. Lamé's formulation was used to find analytical solutions. Pressure transmission can be related to catheter caliber and the compressibility of the urethral tissue (poisson ratio) in a simple mathematical form. The theoretical pressure transmission ratio will be 133% with the additional incompressibility assumption, reflecting the passive structural transmission of intraabdominal pressure increase. The relationship between the pressure measurement error and the catheter caliber was found to be linear (r2 = 0.94 +/- 0.04) and two or more pressure measurements need to be used to find the uninstrumented pressure. It was predicted that collagen implantation treatment might improve the pressure transmission ratio maximally by 33%.     

Breast abscess: coagulase-negative staphylococcus as a sole pathogen

Breast abscesses in nonlactating women are very uncommon. Rarely have cases been reported in which coagulase-negative staphylococci have been isolated in pure culture. We describe a 67-year-old patient who had such an abscess. Specimens obtained by fine needle aspiration, incision and drainage, and biopsy of the breast mass all showed acute inflammation and many gram-positive cocci on gram stain and histologic examination; cultures of all specimens yielded many coagulase-negative staphylococci. The patient responded well to incision and drainage and therapy with antibiotics.     

Uroporphyria induced by 5-aminolaevulinic acid alone in Ahrd SWR mice

In mice, depression of hepatic uroporphyrinogen decarboxylase (UROD) leading to porphyrin accumulation (uroporphyria) occurs with chlorinated ligands of the aryl hydrocarbon (AH) receptor especially after iron overload. However, in the absence of chlorinated ligands, iron itself will eventually cause uroporphyria, but this response is not associated with the Ahr genotype. These effects are potentiated by administration of the haem precursor 5-aminolaevulinate (ALA). The aim of this study was to investigate the effects of ALA alone. Prolonged administration of 2 mg ALA/mL in the drinking water to SWR mice also led to decarboxylase insufficiency (11% of control) and uroporphyria by 8 weeks, whereas DBA/2 mice did not show reduced enzyme activity. Both strains are considered AH nonresponsive and analysis of the Ahr gene using restriction fragment length polymorphism was consistent with SWR, like DBA/2, possessing the Ahrd allele. Exposure of isolated hepatocytes to ALA (150-500 microM) for up to 48 hr showed a significant accumulation of both uroporphyrin and coproporphyrin in the medium, which for uroporphyrin particularly was significantly greater with SWR than with DBA/2 cells. Basal in vivo CYP1A2 activity, measured as microsomal methoxyresorufin dealkylation, was significantly greater in SWR than in DBA/2 mice (1.3-fold), but it was unclear whether this was sufficient to explain the marked difference in sensitivities of the two strains. Despite SWR mice being AH nonresponsive, uroporphyria and decarboxylase depression after an initial iron overload and ALA for 3 weeks were greatly potentiated by a single dose (100 mg/kg) of hexachlorobenzene (a weak AH ligand). The results demonstrate that there is a genetic difference in mice independent of the Ahr genotype and response to iron, which influences the susceptibility to ALA-induced uroporphyria. Thus chemicals, iron and ALA can act independently, but also together, to cause porphyria in susceptible individuals.