Motor fluency makes it possible to integrate the components of the trace in memory and facilitates its re-construction.

The aim of this work was to test the hypothesis that motor fluency should help the integration of the components of the trace and therefore its re-construction. In the encoding phase of each of the three experiments we conducted, a word to be remembered appeared colored in blue or purple. Participants had to read these words aloud and, at the same time, execute a gesture in their ipsilateral (fluent gesture) or contralateral space (non-fluent gesture), according to the color of the word. The aim of the first experiment was to show that the words associated with a fluent gesture during the encoding phase were more easily recognized than those associated with a non-fluent gesture. The results obtained supported the hypothesis. In the second experiment, our objective was to show that the fluency of a gesture performed during encoding in order to associate a word with a color can facilitate the integration of the word with its color. Here again, the results obtained supported the hypothesis. While in Experiment 2 we tested the effect of motor fluency during encoding on word-color integration, the objective of Experiment 3 was to show that motor fluency was integrated in the word-color trace and contributed to the re-construction of the trace. The results obtained supported the hypothesis. Taken together, these findings lead us to believe that traces are not only traces of the processes that gave rise to them, but also traces of the way in which the processes took place.

Emotional responses to pleasant and unpleasant olfactory, visual, and auditory stimuli: a positron emission tomography study.

Neural correlates of responses to emotionally valenced olfactory, visual, and auditory stimuli were examined using positron emission tomography. Twelve volunteers were scanned using the water bolus method. For each sensory modality, regional cerebral blood flow (rCBF) during presentation of both pleasant and unpleasant stimuli was compared with that measured during presentation of neutral stimuli. During the emotionally valenced conditions, subjects performed forced-choice pleasant and unpleasant judgments. During the neutral conditions, subjects were asked to select at random one of a two key-press buttons. All stimulations were synchronized with inspiration, using an airflow olfactometer, to present the same number of stimuli for each sensory modality. A no-stimulation control condition was also performed in which no stimulus was presented. For all three sensory modalities, emotionally valenced stimuli led to increased rCBF in the orbitofrontal cortex, the temporal pole, and the superior frontal gyrus, in the left hemisphere. Emotionally valenced olfactory and visual but not auditory stimuli produced additional rCBF increases in the hypothalamus and the subcallosal gyrus. Only emotionally valenced olfactory stimuli induced bilateral rCBF increases in the amygdala. These findings suggest that pleasant and unpleasant emotional judgments recruit the same core network in the left hemisphere, regardless of the sensory modality. This core network is activated in addition to a number of circuits that are specific to individual sensory modalities. Finally, the data suggest a superior potency of emotionally valenced olfactory over visual and auditory stimuli in activating the amygdala.

Tumor-associated lymphocytes (TAL) are competent to produce higher levels of cytokines in neoplastic pleural and peritoneal effusions than those found in sera and are able to release into culture higher levels of IL-2 and IL-6 than those released by PBMC.

This work was designed to study the proliferative response of tumor-associated lymphocytes (TAL) from neoplastic effusions against autologous tumor cells and the immunophenotype pattern of TAL from neoplastic effusions and that of PBMC of the same patients. We also compared the serum levels of the cytokines interleukin (IL) 1 beta, 2 and 6, tumor necrosis factor-alpha (TNF alpha) and soluble IL-2 receptor (sIL-2R) with those present in neoplastic effusions of the same patients. Moreover, we examined the ability of TAL and peripheral blood mononuclear cells (PBMC) to produce and release the cytokines and sIL-2R and to express membrane CD25 following their stimulation with phytohemagglutinin (PHA) in vitro. Finally, we compared the cytokines/sIL-2R production and membrane CD25 expression by PHA-stimulated PBMC of the patients with neoplastic effusions with a series of 90 cancer patients without neoplastic effusions and 20 normal healthy subjects. Thirteen neoplastic pleural and eight peritoneal effusions were collected from 11 patients with primary lung cancer, 7 with primary epithelial ovarian cancer, 1 with breast cancer, 1 with pleural mesothelioma, and 1 with pancreatic cancer. The proliferative response of TAL from neoplastic effusions against autologous tumor cells was lower than the response to PHA, IL-2, and anti-CD3, but significant. The percentage distribution of CD3+ and CD8+ lymphocyte subpopulations was higher in peritoneal than in pleural effusions, while the CD16+ subset was higher in pleural than in peritoneal effusions. The percentage distribution of CD16+ was significantly lower in pleural effusions than in PBMC of patients with pleural effusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and antitumor activity of ester-modified analogues of bengamide B.

Bengamide B, a novel sponge-derived marine natural product with broad spectrum antitumor activity, was not suitable for further preclinical development because of its difficult synthesis and very poor water solubility. Bengamide B produced a 31% T/C at its solubility-limited maximum intravenous dose of 33 micromol/kg in MDA-MB-435 breast carcinoma implanted subcutaneously as a xenograft in nude mice. Compound 8a, a bengamide B analogue with three structural changes (t-Bu alkene substituent, unsubstituted lactam nitrogen, and inverted lactam 5'-myristoyloxy group), was as potent as bengamide B in vitro and more efficacious than bengamide B in vivo. A series of ester-modified analogues based on 8a were synthesized and tested in vitro and in vivo (MDA-MB-435). The cyclohexyl- and phenethyl-substituted esters, 8c and 8g, respectively, had in vitro and in vivo activities similar to that of 8a and enhanced water solubility (ca. 1 mg/mL). Consequently, 8c and 8g were tested in the MDA-MB-435 xenograft model at 100 micromol/kg and produced 29% and 57% tumor regression, respectively.

Peripheral papillary tumor of type-II pneumocytes: a rare neoplasm of undetermined malignant potential.

Peripheral papillary adenomas of the lung are uncommon neoplasms (only ten cases have been described so far in the English literature) composed predominantly of type-II pneumocytes and generally considered benign. We describe here two additional cases of this lung tumor. In both cases histological examination revealed an encapsulated papillary neoplasm with invasion of the capsule and, in one case, invasion of the adjacent alveoli and visceral pleura too. The proliferative index (Ki67) was less than 2% and the epithelial cells were positive for cytokeratins, surfactant apoproteins (SP), and nuclear thyroid transcription factor-1 (TTF- 1). Ultrastructurally, the epithelial cells showed the characteristic surface microvilli and cytoplasmic lamellar inclusions of type-II cells. Review of the literature has revealed two other cases of peripheral papillary adenoma of type-II pneumocytes with infiltrative features. Thus, we propose replacing the term peripheral papillary adenoma with peripheral papillary tumor of undetermined malignant potential.

Endoscopic laser ablation as palliative treatment of endobronchial, nonresectable, or recurrent lung cancer: assessment of its impact on quality of life.

Laser ablation (LA) is currently used in our institute as palliative treatment for endobronchial nonresectable or recurrent lung cancer. The objective of this study was to assess the impact of LA on the quality of life (QOL) in a large group of patients with endobronchial obstructions due to nonresectable or re-current lung cancer. Evaluation was based on Eastern Cooperative Oncology Group performance status (ECOG PS) for the "objective" assessment of QOL and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 version 1.0 (EORTC QLQ-C30(v1)) for the "subjective" assessment of QOL. From May 1994 to June 1997, 133 LAs were performed using neodymium: yttrium-aluminum garnet (Nd:YAG) laser at low power settings (< 30W) on 89 evaluable patients (Male/Female 78/11, mean age 63.5/62.8 years, range 42-82/47-73). The QOL was evaluated by ECOG PS and QLQ-C30(v1) at baseline (3 days before LA), t1 (7 days after LA), and t2 (1 month after LA). The objective tumor response was evaluated at t2. The objective tumor response to LA intervention was "excellent," ie, complete response (CR), in 33 (24.8%) patients and "fair," ie, partial response (PR), in 97 (72.9%) patients, with an overall response rate (ORR) of 97.7%. A highly significant decrease in high score (ECOG PS 3-4) was registered from baseline to t1 and from t1 to t2. However, at the same time a significant increase of low score (ECOG PS 0-2) was observed. The comparison of patient QOL assessment by QLQ-C30(v1) at different times during the study was also made; the functioning scales, the global QOL scale, and the symptom scales/items showed a highly significant improvement at t1 compared to baseline (P < 0.001), whereas only global QOL improved at t2 compared to t1. A comparison of baseline ECOG PS scale with QLQ-C30(v1) scale revealed a strong relationship between PS and the symptom "fatigue." Our study demonstrates that dramatic clinical improvement obtained by an effective though palliative treatment such as LA improves QOL based on both physician-rated (PS) and mostly self-rated (QLQ-C30(v1)) assessment.

Relationships betxween Fas expression, activation molecule CD25, and functional activity of tumor-associated lymphomonocytes from neoplastic effusions.

Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas bearing cells. In the present study we assessed the expression of Fas, activation molecule interleukin (IL)-2 receptor alpha chain (CD25) and an index of functional activity such as thymidine uptake under mitogen stimulation of tumor associated lymphomonocytes (TALM) from 7 neoplastic effusions of advanced cancer patients. The same parameters were studied in peripheral blood mononuclear cells (PBMC) of 7 patients with cancer of different sites and in 7 normal subjects. The proliferative response to phytohemagglutinin (PHA), measured as [3H]-thymidine uptake, of TALM was significantly lower than that of PBMC of cancer patients. The expression of CD25 on unstimulated fresh TALM was slightly higher than that of PBMC from normal subjects: after 24 h of PHA stimulation the CD25 was expressed both on TALM and PBMC from normal subjects. The expression of Fas was assessed on unstimulated TALM, PBMC from cancer patients and normal subjects immediately after (by 2 h, t0) the cell separation, and at different times (24 h and 48 h) thereafter, and on PHA-stimulated TALM, PBMC from cancer patients and normal subjects after 24 h and 48 h of culture (in RPMI 1640). At all times (t0, 24 h and 48 h) the Fas expression by unstimulated TALM was significantly higher than that of PBMC from normal subjects: the Fas expression by PBMC from cancer patients was roughly in the same range as PBMC from normal subjects. At 24 h the Fas expression by PHA-stimulated TALM was significantly higher than that of PBMC from normal subjects, whereas at 48 h the difference was not significant. The TALM studied by us showed to be functionally defective and expressing relatively high levels of Fas showing the characteristics to be considered as a target for FasL expressing tumor cells, which in this way may escape immune control.

Negative priming in a gender decision task and in a semantic categorization task.

In three experiments, we tested the hypothesis that negative priming (NP) can occur without prime or target selection, when conflicting properties are associated with the prime and the target, and when the experimental conditions allow the encoding of the target as a separate episode from the prime. These predictions were confirmed in Experiment 1, using a gender decision task. Responses were slower when prime and target had the same gender than when they had different genders, with an inter-stimulus interval (ISI) of 600 ms but not with an ISI of 25 ms. Experiment 2 eliminated a possible explanation of the NP obtained in Experiment 1, in terms of response inhibition during the prime processing. Finally, Experiment 3 demonstrated the replicability and the generality of our NP, in a semantic categorization task. Empirical and theoretical consequences of our results for studies using the priming paradigm are discussed.

Emotional states, attentional resources, and cognitive activity: a preliminary study.

This study explored the link between emotional state and attentional resources. A neutral or negative emotional state was induced in 50 subjects, then they performed a path-learning task followed by a word-memorization task while reproducing the prelearned path. Memory performance was assessed on a free-recall test. Analysis indicated that a previous induction of a negative emotional state disrupted path learning. Recall was not significantly affected by the subjects' emotional states, but recall was higher for subjects who had automatized the path prior to memorizing the words.

[Empyema due to an anaerobic Streptococcus in childhood]. / Empiema da streptococco anaerobio in età infantile.

Anaerobic infections are quite rare in pediatric age, being that, they affect only neonates and immunodepressed patients. We think to be somewhat interesting to describe the case of our patient, a 9 year old boy, unaffected by any predisposing factor, came under our observation because of a severe respiratory distress. He showed evident clinical and radiological signs of pleural effusion in the right lung, together with a gas coil in the upper field and a left mediastinal shifting. A thoracentesis was then performed, giving rise to 600 ml of foul smelling purulent material; this procedure promptly improved his respiratory function. A permanent drainage trough the chest wall was set and an antibiotic therapy, based on the clinical picture and the character of the exudate, begun. In effect, the typical smell of the purulent material led us to suspect an anaerobic infection, and for this reason we employed the teicoplanin iv, a rarely used in the pediatric age drug. While blood cultures were negative for any organism, exudate cultures yielded Peptostreptococcus anaerobius; the last one resulted highly sensible following antibiogram to the previously chosen drug. The x-ray pattern and the rapid disappearing of the gas coil induced us to exclude further either congenital or acquired lung diseases. We conclude that, in absence of other proved sources of entry, the air presence in the pleural space was secondary to gas formation by the anaerobic micro-organism. The clinical course was very satisfactory allowing the patient to be dismissed on the 28th hospital day, with no need of further surgical therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Results of a dose-intense phase 1 study of a combination chemotherapy regimen with cisplatin and epidoxorubicin including medroxyprogesterone acetate and recombinant interleukin-2 in patients with inoperable primary lung cancer.

Based on the role of cytokines in the pathogenesis of cancer-related anorexia-cachexia and the ability of progestins, such as medroxyprogesterone acetate, to reduce cytokine production and relieve cancer-related anorexia-cachexia symptoms, the authors designed an open, dose-finding phase I study of a combined chemotherapy regimen (cisplatin [CDDP], epidoxorubicin [EPI]), including recombinant interleukin-2 (IL-2) and medroxyprogesterone acetate for patients with stage IIIB to IV inoperable primary lung cancer. The end points were clinical response and toxicity with definition of dose-limiting toxicity and maximal tolerable dose; relief of cancer-related anorexia-cachexia symptoms; the assessment of patient serum levels of IL-1beta, IL-6, tumor-necrosing factor-alpha (TNF-alpha), and soluble IL-2 receptor (sIL-2R). From March to October 1997, 16 patients (M:F ratio, 14:2; mean age, 60.5 years; age range, 41 to 74 years) were enrolled. All patients were evaluable for toxicity and 14 of them for response. The patients were assigned to increasing dose levels of drugs according to a dose-escalation schedule. The weekly schedule consisted of a combination of CDDP given intravenously on day 1, EPI given intravenously on day 1, 1 g/day medroxyprogesterone acetate given orally on days 1 to 7, and recombinant IL-2 1.8 MIU administered subcutaneously on days 2 to 7 plus 300 microg granulocyte-colony stimulating factor support given subcutaneously on days 2 to 5. Administration of medroxyprogesterone acetate began 1 week before the first cycle. Dose escalation of the drugs was as follows: 30 mg x m2 x week(-1) CDDP and 25 mg x m2 x week(-1) EPI (first level, two patients); 30 mg x m2 x week(-1) CDDP and 33 mg x m2 x week(-1) EPI (second level, 2 patients); 40 mg x m2 x week(-1) CDDP and 33 mg x m2 x week(-1) EPI (third level, 6 patients); and 40 mg x m2 x week(-1) CDDP and 40 mg x m2 x week(-1) EPI (fourth level, 6 patients). Six cycles were planned for each patient. The actual dose intensity delivered was more than 80% of the projected dose intensity of all drugs. After six cycles, clinical response (according to World Health Organization criteria), toxicity (according to World Health Organization criteria), Eastern Cooperative Oncology Group (ECOG) performance status, body weight, appetite, and serum levels of cytokines were evaluated. After six cycles, 9 of 14 patients (64.3%) had partial response, 3 of 14 (21.4%) had stable disease, and 2 of 14 (14.3%) had progressive disease, and the objective response rate was 64.3%. ECOG performance status and body weight did not change significantly after treatment, whereas appetite showed an increase that was of borderline statistical significance. Toxicity was acceptable and only hematologic. Dose-limiting toxicity was established at the fourth dose level; consequently, maximal tolerable dose was assessed at the third dose level. Before treatment, the serum levels of IL-1beta, IL-6, and TNF-alpha were significantly greater in the patients than in healthy persons. The comparison between pretreatment and posttreatment serum values of IL-1beta, IL-6, TNF-alpha, and sIL-2R did not reveal significant differences in the patients. Similar results were obtained when the patients were considered as responders (partial response) or non-responders (stable or progressive disease) to therapy. Only IL-6 serum levels were increased (p = 0.014) after treatment.

Tumor-associated lympho-monocytes from neoplastic effusions are immunologically defective in comparison with patient autologous PBMCs but are capable of releasing high amounts of various cytokines.

We studied several in vitro activities of tumor-associated lympho-monocytes (TALMs) and the concentrations of interleukin (IL)-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)alpha, interferon (IFN)gamma and soluble IL-2 receptor (slL-2R) in neoplastic effusions and in the serum of advanced stage cancer patients. Comparisons were made with autologous peripheral blood mononuclear cells (PBMCs). Autologous PBMCs were compared with PBMCs from normal subjects used as controls. TALMs were collected from 13 peritoneal and 18 pleural neoplastic effusions, secondary to primary tumors of different sites. After PHA stimulation, concentrations of IL-1alpha, IL-1beta and TNF alpha in culture media of TALMs both from peritoneal and pleural effusions were lower than those of autologous PBMCs and, similarly, concentrations of IL-4 and IL-10 in culture media of TALMs from peritoneal effusions were lower than those of autologous PBMCs, whereas concentrations of IL-4 and IL-10 in culture media of TALMs from pleural effusions were in the same range as those of autologous PBMCs. On the contrary, IL-2, IL-6 and IFN gamma amounts (only from pleural effusions) were significantly higher. IL-1alpha, IL-1beta, IL-2, IL-6 and TNF alpha production from patient PBMCs was lower than that of control PBMCs, whereas production of IL-4, IL-10 and IFN gamma was higher than that of control PBMCs. Both in peritoneal and in pleural effusions concentrations of IL-1alpha, IL-1beta and IL-4 were not different from those measured in autologous serum, whereas those of IL-6, IL-10, TNF alpha, IFN gamma and sIL-2R were significantly higher. The amounts of IL-2 in pleural effusions were not different from those of autologous serum, but in peritoneal effusions they were higher than those of autologous serum. The amounts of IL-1alpha, IL-1beta, IL-2, IL-6, TNF alpha and sIL-2R were higher in patient than in control sera, whereas those of IL-4, IL-10 and IFN gamma were in the same range in patient and in control sera. Cell cycle analysis of cultured TALMs and PBMCs (from 3 patients) showed a significant accumulation of TALMs in the non-cycling G0/G1 cell population compared with autologous PBMCs.

In vitro metabolism of N-(5-chloro-2-methylphenyl)-N'-(2-methylpropyl)thiourea: species comparison and identification of a novel thiocarbamide-glutathione adduct.

The in vitro metabolism of SDZ HDL 376, a thiocarbamide developed for the treatment of atherosclerosis, was investigated in rat, dog, monkey, and human liver microsomes, as well as in rat and human liver slices. [14C]SDZ HDL 376 was extensively metabolized in all the species except human. In rat liver microsomes an S-oxide was the major metabolite. In human and monkey microsomes, carbon hydroxylation was favored. The NADPH-dependent oxidation of SDZ HDL 376 resulted in covalent binding to microsomal protein. Addition of GSH to the incubations decreased protein binding in a concentration-dependent manner and resulted in a novel SDZ HDL 376-GSH adduct. Adduct formation required NADPH and was mediated predominantly by cytochrome P450. Inhibition of cytochrome P450 by 1-aminobenzotriazole resulted in a 95% decrease in adduct formation, while heat inactivation of flavin-containing monooxygenases resulted in a 10% decrease. Unlike other thiocarbamides which form disulfide adducts with GSH, the SDZ HDL 376 adduct contained a thioether linkage as characterized by LC/MS/MS and reference to a synthetic standard. Reactions performed with [35S]GSH resulted in a [35S]SDZ HDL 376-GSH adduct, demonstrating the sulfur was derived from GSH. Adduct formation was faster in rat microsomal reactions compared to human microsomes. Other structurally unrelated thiocarbamides (phenylthiourea, methimazole, 2-mercaptobenzimidazole, 2-mercaptoquinazoline, and 2-propyl-6-thiouracil) did not form similar adducts in rat liver microsomes supplemented with GSH. Therefore, the GSH adduct of SDZ HDL 376 is unique for this type of thiocarbamide. These results suggest that the bioactivation and detoxification of SDZ HDL 376 differ significantly from other thiocarbamides. Furthermore, the in vitro formation of S-oxides and GSH adducts in rat hepatic tissue, and ring hydroxylation and glucuronidation in human hepatic tissue, suggests rats may be more susceptible to the toxicity of SDZ HDL 376 compared to humans.

Bengamides revisited: new structures and antitumor studies.

The structural chemistry and biological activity of the bengamide class of compounds have been further characterized. Extracts prepared from recollected Jaspis cf. coriacea from five sites in Fiji were pooled. Six new bengamides, M (7b), N (8a), O (8b), P (9a), Q (9b), and R (10), were identified, accompanied by the known bengamides A (1a), B (1b), E (3a), F (3b), Y (5), Z (6), L (7a), G (11a), H (11b), and I (12). The structures of the new compounds were determined from spectroscopic data, and some were additionally confirmed by semisynthesis. Cytotoxicity screening data were obtained from the NCI-DTP 60 cell screen for bengamides A, B, and P. Bengamides A and B were more potent than bengamide P, with average IC(50) values of 0.046, 0.011, and 2.70 FM, respectively. The in vitro antitumor activity against MDA-MB-435 human mammary carcinoma was also determined for natural bengamides A, B, E, F, P, M, O, and Z and for synthetic samples of B and O. The best activity was observed for the natural bengamides A (IC(50) = 1 nM) and O (IC(50) = 0.3 nM).

Total syntheses of bengamides B and E.

Total syntheses of the cytotoxic marine natural products bengamides B and E are described. Both bengamides are prepared via amide coupling of a protected polyhydroxylated lactone intermediate 9 with a suitably substituted aminocaprolactam intermediate. Lactone 9 is prepared in five steps from commercially available alpha-D-glucoheptonic gamma-lactone. The key reactions are a selective deprotection of a 1,2-acetonide in the presence of a 1,3-acetonide and an (E)-selective olefination of an unstable aldehyde using a gem-dichromium reagent. The bengamide B lactam intermediate 10 is prepared in seven steps from commercially available (5R)-5-hydroxy-L-lysine (12). The desired S-configuration at the gamma-OH lactam position is established using the Mitsunobu reaction.