Functional Anatomy of Visuomotor Skill Learning in Human Subjects Examined with Positron Emission Tomography

The present study was designed to examine patterns of regional cerebral blood flow (CBF) associated with the learning of a repeated visuomotor sequence both in the early and late phases of the acquisition process. In addition, changes in blood flow related to the implicit versus explicit aspects of learning such a skill were investigated. Fourteen normal control subjects were scanned while performing the task (i) in both early and advanced learning stages of the visuomotor sequence; (ii) after having acquired explicit knowledge of the sequences; and (iii) in two control conditions (perceptual and random sequence). Subtraction of the random condition from the highly learned condition revealed specific areas of activity in the right ventral striatum and dentate nucleus of the cerebellum. Blood flow changes in the right hemisphere were also seen in the medial posterior parietal and prestriate regions, as well as in the anterior cingulate cortex. Finally, once the subjects had acquired explicit knowledge of the embedded sequence that was presented in the highly learned condition, increased CBF activity was observed only in the mid-ventrolateral frontal area in the right hemisphere. These findings confirm that both the striatum and the cerebellum are involved in the implicit acquisition of a visuomotor skill, especially in the advanced stages of the learning process, and furthermore that the ventrolateral prefrontal cortex contributes preferentially to the declarative aspect of this task.     

Endokrine Therapie solider Tumoren

Zum Thema Medikamente, die in hormonelle Regelkreise eingreifen, werden wegen ihrer hohen Wirksamkeit und guten Vertr?glichkeit bei hormonsensitiven Tumoren wie Mamma-, Prostata- und dem Endometriumkarzinom eingesetzt. Ziel aller hormonellen Behandlungsma?nahmen ist die Ausschaltung der hormonbedingten Wachstumsstimulation durch Blockade der Hormonproduktion oder Hemmung der Hormonwirkung auf zellul?rer Ebene. Dies erfolgt bei postmenopausalen Frauen mit Brustkrebs durch Aromatasehemmstoffe, bei pr?menopausalen, ebenso wie bei Patienten mit Prostatakarzinom durch GnRH-Analoga. Eine neue Generation von Aromatasehemmstoffen zur Behandlung des Brustkrebses weist nicht nur bessere Vertr?glichkeit und Wirksamkeit auf, sondern bedeutet auch einen überlebensvorteil für die Patientinnen. Anti?strogene sind bei pr?- und insbesondere bei postmenopausalen Patientinnen sowohl in der adjuvanten, als auch in der palliativen Behandlungssituation wirksam. Aufgrund ihrer guten Vertr?glichkeit wurden sie bei Frauen mit erh?htem Brustkrebsrisiko mit Erfolg zur Pr?vention eingesetzt. Bei Patienten mit Prostatakarzinom hat die sog. komplette Androgenblockade (chirurgische oder medikament?se Ausschaltung der Testesfunktion und gleichzeitige Antiandrogengabe) die Hoffnung auf bessere Krankheitskontrolle nicht erfüllen k?nnen.     

Modulation of murine Peyer''s patch immunoglobulin A response by enterotoxigenic Escherichia coli.

Enterotoxigenic Escherichia coli (ETEC) may have profound effects on the capacity of gut-associated lymphoid tissue to mount a secretory immune response because of the potential ability of heat-stable toxin or heat-labile toxin to modulate the immune response. To examine the effects of ETEC or its purified enterotoxins upon the humoral immune response of murine small intestinal Peyer's patch lymphocytes, BDF1 (lipopolysaccharide-responder) and C3H/HeJ (lipopolysaccharide-nonresponder) mice were orally primed with sheep erythrocytes (SRBC) four times during a 2-week period to initiate differentiation of Peyer's patch B lymphocytes to cells committed to anti-SRBC immunoglobulin A (IgA) production. Halfway through the oral priming regimen the mice were gastrically intubated with 10(8) ETEC, 10(8) non-ETEC, or saline. ETEC persisted in the small intestine for at least 7 days at a level of 10(3) to 10(4) bacteria per mouse. Seven days after the last oral dosing with SRBC, Peyer's patch lymphocytes were removed from infected or saline-treated mice and incubated in vitro with SRBC. The ETEC infection had a small effect on the anti-SRBC IgM plaque-forming cell response of SRBC-primed mice but inhibited significantly the anti-SRBC IgA plaque-forming cell response in both BDF1 and C3H/HeJ mice as compared with uninfected controls. The non-ETEC, an isolate from normal mouse small intestine, had no significant effect on either IgM or IgA anti-SRBC plaque-forming cell response. Purified heat-labile toxin, not heat-stable toxin, alone in a dose-dependent manner significantly inhibited both the IgA and IgM plaque-forming cell response of Peyer's patch lymphocytes from primed mice. These data suggest that ETEC can inhibit the development of the gut-associated lymphoid tissue IgA immune response through the immunopharmacological effect of an enterotoxin, the heat-labile toxin.     

Effect of Dietary Essential Amino Acid Limitations upon the Susceptibility to Salmonella typhimurium and the Effect Upon Humoral and Cellular Immune Responses in Mice

We investigated the effects of dietary essential amino acid limitations on the susceptibility of mice to Salmonella typhimurium infections and on humoral and cellular immune (cell-mediated immune) responses of mice. Mice fed synthetic diets limited (significantly less than optimum concentration) in a single essential amino acid (leucine, isoleucine, valine, or lysine) for 3 weeks after they were weaned exhibited significantly enhanced susceptibility to S. typhimurium infection, as evidenced by the higher levels of mortality and spread of the bacterial cells in their livers and spleens compared with mice fed the control diet. Compared with mice fed the control diet, mice fed the diet limited in leucine had a lower ability to clear S. typhimurium cells from the peritoneal cavity 5 min after intraperitoneal injection, whereas mice fed the diet limited in lysine had a greater ability. The in vivo phagocytosis and in vitro bactericidal kinetics against S. typhimurium cells by peritoneal macrophages were not significantly different in the control group and the groups of mice fed experimental diets. Certain experimental groups exhibited significantly lower resistance and antibody response against S. typhimurium SL3770 on day 5 after immunization with heat-killed S. typhimurium SL3770. On day 8 after immunization, the levels of serum antibody against S. typhimurium in the mice fed the experimental diets were comparable to the levels in mice fed the control diet. However, the levels of serum transferrin and complement C3 were significantly lower in mice fed certain experimental diets. The cellular immune capacities of mice fed any of the experimental diets were not impaired compared with the capacities of mice fed the control diet, as measured by spleen cell responsiveness to phytohemagglutinin and the ability to clear infecting Listeria monocytogenes cells from livers and spleens.     

Peptides derived from IgE heavy chain constant region induce profound IgE isotype-specific tolerance

(BALB/c × SJL)F1 mice, perinatally injected with peptide-N-glyconase F-treated, deglycosylated IgE heavy chain or recombinant IgE heavy chain (CH?2-CH?4), were profoundly inhibited in antigen-specific IgE production. There exist minimally two tolerogenic IgE peptides, residing in the CH?2 and CH?4 domains. Peptide I, generated by V8 protease, comprises 39 amino acids within CH?2, beginning at amino acid 103. Peptide E begins at amino acid 312 of the CH?4 domain and extends through the CH?4 domain. The total lack of antigen-specific IgE responses in IgE peptide-treated mice was not due to overproduction of interferon-γ, nor lack of interleukin (IL)-4, as predicted by the Th2/IL-4 paradigm for IgE production. IgE-tolerant mice exhibited comparable levels of circulating anti-IgE antibodies to those of PBS-treated control mice. IgG obtained from sera of both sources failed to inhibit IgE responses in vitro. Moreover, IgE responses of spleen cells from IgE peptides-treated mice were restored by CD4⁺ T cells from PBS-treated control mice. We hypothesize that regulation of antigen-specific IgE responses is mediated by CD4⁺ T cells which normally recognize IgE peptides on IgE precursor B cells, and can be rendered tolerant by perinatal IgE peptide treatment.     

Smokeless tobacco and nicotine bring about excessive cytokine responses of murine memory T-cells

To determine the influence of smokeless tobacco (ST) and nicotine on the cytokine phenotype of memory T-cells, splenic mononuclear cells (SPM) were exposed to 1:10(2) or 1:10(3) dilutions of ST extract (ST-SPM), 10 or 100 microg/ml nicotine (NIC-SPM), or medium (CON-SPM) during 4 days of stimulation with anti-CD3. SPM were then washed extensively to remove residual ST or nicotine and restimulated with anti-CD3 and anti-CD28 in the absence of ST or nicotine. Expression of IL-2, IL-4, IL-10 and IFN-gamma protein and mRNA levels after 4 days of primary stimulation and after 24 and 48 h of restimulation was evaluated using ELISA and RT-PCR, respectively. After 4 days of primary stimulation, SPM exposed to 100 microg/ml nicotine sustained expression of IL-2, IFN-gamma, IL-10 and IL-4 mRNA as opposed to CON-SPM. Restimulation of CON-SPM resulted in maximum re-expression of cytokine mRNA at 24 h and a decline by 48 h. Restimulated NIC-SPM in the absence of nicotine delayed maximal re-expression of IL-2, IFN-gamma, IL-10 and IL-4 mRNA until 48 h. Heightened expression of cytokine mRNA at 48 h was paralleled by a small but significant increase in production of IFN-gamma, IL-4 and IL-10 protein by NIC-SPM as measured by ELISA. In contrast, ST-SPM did not exhibit residual expression of cytokine mRNA after 4 days of primary stimulation. Like NIC-SPM, however, restimulated ST-SPM exhibited maximum IL-2, IL-4, IFN-gamma, and IL-10 mRNA at 48 h. Heightened re-expression of cytokine mRNA at 48 h by ST-SPM was paralleled by increased production of IL-2, IFN-gamma, IL-4 and IL-10 protein. These results indicate that exposure of T-cells to nicotine, but not ST, during a primary immune response result in inordinate cytokine expression after 4 days. In addition, memory T-cells initially exposed to nicotine or ST during a primary immune response, exhibit excessive cytokine expression when T-cells are restimulated in the absence of nicotine or ST. pharmacology.     

Fiber system linking the mid-dorsolateral frontal cortex with the retrosplenial/presubicular region in the rhesus monkey

The present study investigated the origin, course, and terminations of the association fiber system linking the frontal cortex with the hippocampal system by means of the cingulum bundle. Injections of tritiated amino acids were placed within individual cytoarchitectonic areas of the frontal cortex in the rhesus monkey. It was demonstrated that the mid-dorsolateral frontal cortex (areas 46, 9/46, and 9) and its medial extension (medial areas 9 and 9/32) is the origin of a specific fiber pathway, running posteriorly as part of the cingulum bundle, and terminating mainly in the retrosplenial area 30 and the posterior presubiculum. This fiber bundle therefore provides the anatomical substrate of a functional interaction between the mid-dorsolateral frontal cortex and the hippocampal memory system for the monitoring of information within working memory.     

Caffeine Pretreatment Enhances Clinical Efficacy and Reduces Cognitive Effects of Electroconvulsive Therapy

In an open clinical trial, depressed patients received age-dosed, brief-pulse electroconvulsive therapy (ECT) either with or without 500 mg i.v. caffeine sodium benzoate before each treatment. Caffeine-pretreated patients required fewer ECT treatments, and after three to four treatments, their Hamilton Depression Scale (HDS) scores were significantly lower. At the end of the ECT course, both groups reached the same reduction in HDS scores. Of five memory tests, one showed better performance at the end of the ECT course for the caffeine-pretreated compared with the non-caffeine-pretreated patients. The results argue that caffeine-modified ECT differs from unmodified ECT in speed of response and the effects on cognitive tests.