Exchange protein activated by cyclic AMP 2 (Epac2) plays a specific and time‐limited role in memory retrieval

Knowledge on the molecular mechanisms involved in memory retrieval is limited due to the lack of tools to study this stage of the memory process. Here we report that exchange proteins activated by cAMP (Epac) play a surprisingly specific role in memory retrieval. Intrahippocampal injection of the Epac activator 8‐pCPT‐2′O‐Me‐cAMP was shown to improve fear memory retrieval in contextual fear conditioning whereas acquisition and consolidation were not affected. The retrieval enhancing effect of the Epac activator was even more prominent in the passive avoidance paradigm. Down‐regulation of Epac2 expression in the hippocampal CA1 area impaired fear memory retrieval when the memory test was performed 72 h after training, but not when tested after 17 days. Our data thus identify an important time‐limited role for hippocampal Epac2 signaling in cognition and opens new avenues to investigate the molecular mechanisms underlying memory retrieval. © 2009 Wiley‐Liss, Inc.     

Work-related skin and airway symptoms among Swedish dentists rarely cause sick leave or change of professional career.

Dentistry usually is 'wet work' with risk of damage to the skin barrier, and the hands may be exposed to skin irritants and contact-sensitizing substances used in dental materials or gloves. Airway irritants may also be present. This study assessed the consequences of work-related skin and airway symptoms among dentists in terms of contact with health authorities, sick leave, or changes in the professional career. A questionnaire on these factors was answered by more than 3000 Swedish dentists. Only 6% of the respondents had consulted a physician, although 22% had noted work-related skin symptoms. In 2% the skin symptoms had caused sick leave, and about 2% had reported their skin symptoms as an occupational disease. Two per cent had consulted a physician owing to work-related airway symptoms, which is a minor part of the 13% who had experienced such symptoms when in contact with dental materials. Twenty-five dentists (<1%) had been on sick leave because of work-related airway symptoms. Only 1 dentists reported change of activities or occupation owing to work-related skin or airway symptoms, and in most cases these symptoms only contributed to their decision. In summary, whereas sick leave in dentists because of musculoskeletal problems may be common, the present study shows that this is not the case for work-related skin or airway symptoms, and such symptoms seldom affect the dentists' professional career.     

Model for time dependency of cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action.

CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorometric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation. Patterns of change of drug potency (IC(50)), slope of the concentration-effect curves, and plateau with time were studied. The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC(50) for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC(50) for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC(50) and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death.     

Brain strategies for reading in the second language are determined by the first language

Brain activation associated with reading was investigated in ten normal Japanese volunteers (five highly literate in both Japanese and English) and ten American native English speakers (five highly literate in both English and Japanese) in order to determine the neuroanatomic substrates employed in reading the first language (L1), and to determine the effect of L1 on the neurosubstrates involved in reading the second language (L2). The study was performed using blood oxygenation level dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) on a high-field (3.0T) system specifically optimized for fMRI. The activation patterns in Japanese subjects reading Japanese (L1) were substantially different from the patterns obtained in American subjects reading English text (L1). The activation patterns reading L2 were virtually identical to the patterns seen when reading L1 in both Japanese and English natives highly literate in both language systems. The results demonstrated that the neuroanatomical substrates underlying the cognitive processing of reading are differentially determined based on the language system. The study further indicates that the cognitive processes for reading in the second language involve the same cortical structures employed for the first language, supporting the hypothesis that the second language represents the cognitive extension of the first language.     

Plexus avulsion and spinal cord injury increase the serum concentration of S-100 protein: an experimental study in rats.

The possibility of using the presence of the glial-cell-derived protein S-100 in serum as a marker for neuronal damage caused by spinal cord injury and plexus avulsion injury was investigated in 144 adult rats. After a spinal cord injury had been induced at the thoracic level or a plexus avulsion injury at the lumbar level, blood samples were taken and analysed for S-100 protein by a monoclonal two-site immunoluminometric assay. The two types of neurotrauma changed the kinetics of serum S-100 in different ways. After spinal cord injury it rapidly increased and within 72 hours had reached a concentration about 5 times that of the control animals. Three peak concentrations occurred at 3, 12, and 72 hours, respectively, and differed significantly from those of the control group (p < 0.05). After six days the values had returned to normal. After lumbar plexus injury alone there was no significant increase in the concentration of S-100. These results suggest that the concentration of S-100 protein in serum may be used as an early diagnostic tool for detecting neuronal damage caused by spinal cord injury or plexus avulsion associated with damage to the root entry zone.     

Cancer Treatment in Sweden - Costs of Drugs, Inpatient and Outpatient Care from 1985 to 1996 and Cost Effectiveness of New Drugs

This study was carried out to investigate the direct costs for treatment of patients with cancer from 1985 to 1996 in Sweden, and to examine health economic effects of changes in treatment pattern. Material for the study was collected from official statistics and from published health economic evaluations of cancer treatment. Costs for inpatient care decreased during the period, while costs for outpatient care and drugs increased. In total, the direct health care costs for cancer treatment decreased from 1985 to 1996. New drugs registered on the market are often more expensive than the drugs they replace. From a health economic perspective it is not clear, however, that higher drug costs necessarily increase total costs. Further health economic research is needed because many treatment alternatives have not yet been evaluated, and furthermore, because a treatment option can be cost effective in one specific indication but not in another.     

Polylactones, 19. Anionic polymerization of L-lactide in solution

The anionic polymerization of L-lactide was studied with four potential initiators of different basicity: potassium benzoate, potassium phenoxide, potassium tert-butoxide and butyllithium. Regardless of the solvent, only the two most basic initiators proved to be reactive enough to initiate and maintain the polymerization. This result and the formation of benzyloxy end-groups upon addition of benzyl bromide prove that the polymerizations proceed via alkoxide chain ends. Absence of initiator fragments in the isolated polylactide chains suggests that initiation mainly involves deprotonation of L-lactide, whereas nucleophilic substitution only occurs to a minor extent. Furthermore, optical rotation measurements indicate that both the initiator and the alkoxide chain end cause partial racemization regardless of solvent and temperature. Furthermore, it was found that reagents such as triethylamine, pyridine or potassium benzoate which are not reactive enough to initiate polymerization, are basic enough to cause partial racemization of L -lactide by deprotonation.     

Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk

The hygiene hypothesis implies that the increasing prevalence of allergy in 'westernized' countries is explained by reduced bacterial exposure in early life, but the underlying mechanism remains elusive. We therefore wanted to study the effect of bacterial lipopolysaccharide (LPS) on the generation of regulatory T (T(R)) cells in neonates, and to analyze differences between neonates with allergy risk because of a family history of atopy (FH+) and controls without such hereditary risk (FH-). Cord blood mononuclear cells from the FH+ and FH- groups were stimulated with beta-lactoglobulin in the presence of LPS. T-cell phenotypes suggestive of T(R) cells [CD25+, CD25high and integrin (CD103+)], and the intracellular proliferation antigen Ki-67 were quantified by flow cytometry. Release of the immunosuppressive cytokine transforming growth factor beta1 (TGF-beta1) from its inactive complex was determined by enzyme-linked immunosorbent assay. The analyses revealed the generation of T-cell phenotypes suggestive of T(R) cells including a CD25high T-cell subset which was inversely related to T-cell proliferation (r=-0.54, p<0.05) and to activation-induced release of TGF-beta1 (r=-0.80, p<0.001). The CD25high T-cell subset tended to be impaired in the FH+ group (% of CD3+ T cells: FH+, 5.1% vs. FH-, 12.6%), and notably, the FH+ group showed a significantly reduced capacity for generation of both CD25+ (FH+, 16.2% vs. FH-, 34.9%; p<0.01) and T cells (FH+, 2.1% vs. FH-, 3.9%; p<0.05). Our findings suggested that early-life exposure to a dietary antigen in the presence of LPS might modulate the immune system by generating T(R) cells. This capacity was impaired in neonates with hereditary allergy risk, but clinical follow-up will be required to determine a possible effect on allergy emergence.     

Das unilaterale laterothorakale Exanthem Kasuistik und Literaturübersicht Kasuistik und Literaturübersicht

Wir berichten über ein unilaterales laterothorakales Exanthem (ULE) bei einem 4j?hrigen Jungen mit einer akuten lymphatischen Leuk?mie in der Erhaltungstherapiephase; es ist der 2. Fallbericht über die Assoziation eines ULE mit Leuk?mie. Die Pathogenese der Erkrankung ist bislang unbekannt. Gelegentlich endemisches Auftretens, h?ufige Assoziation mit Infektionen der oberen Atemwege und das Auftreten bei immunkomprimierten Patienten wie in unserem Fall sprechen für eine virale Genese des ULE. Anhand dieser Kasuistik wird ein überblick über das Krankheitsbild gegeben.     

Population differences in the pattern of familial aggregation for sex hormone‐binding globulin and its response to exercise training: The HERITAGE family study

Familial influences were investigated for baseline sex hormone‐binding globulin (SHBG) and its response (post‐training minus baseline) to a 20‐week endurance exercise training program. One hundred, eighty‐four participants from 85 Black families in the HERITAGE Family Study (HERITAGE) were analyzed using a familial correlation model. Baseline SHBG values and the training response were adjusted for the effects of age, baseline BMI, testosterone, estradiol, and fasting insulin levels (plus baseline SHBG values for the training response) within four sex‐by‐generation groups prior to genetic analysis. Baseline SHBG levels were influenced by appreciable familial effects (maximum heritability h² = 54%) with neither spouse resemblance nor sex and generation differences in the correlations. This estimate is only slightly, but not significantly, smaller than the heritability of 64% reported previously in 428 participants from 99 White families in HERITAGE. In contrast to the modest familial effects for the training response in White participants in HERITAGE (h² = 25%), there were no evidence of familial resemblance in Blacks in the current study. Furthermore, there was heterogeneity for both baseline SHBG and the training response between Blacks and Whites in the pattern of familial aggregation. In conclusion, baseline SHBG levels are influenced by significant familial effects in both Blacks and Whites, independent of the effects of age, sex, and baseline values of BMI, testosterone, estradiol, and fasting insulin levels. Whereas modest familial effects were detected for the training response in Whites, the lack of similar effects in Blacks may be due to the smaller sample size. Am. J. Hum. Biol. 13:832–837, 2001. © 2001 Wiley‐Liss, Inc.