The normative dimension of social life from a second-person perspective

This thesis argues that insofar as we want to account for the normative dimension of social life, we must be careful to avoid construing that normative dimension in such a way as to exclude that which the second-person perspective reveals is important to social life and our ability to participate in it.¦The second-person perspective reveals that social life ought to be understood as a mix or balance of the regular and the irregular, where, in addition, those one interacts with are always to some extent experienced as other in a way that is neither immediately, nor perhaps ultimately, understandable. For persons to be able to participate in social life, conceived of in this way, they must have abilities that allow them to be, to some extent, hesitant and tentative in their relations with others, and thus tolerant of ambiguity, uncertainty and unpredictability, and responsive to and capable of learning from the otherness of others in the course of interacting with them.¦Incorporating the second-person perspective means we have to make some changes to the way we think about the normative in general, and the normative dimension of social life in particular. It does not mean giving up on the distinction between the normative and the regular - that continues to be fundamentally important but it does mean not excluding, as part of social life and as worthy of explanation, all that which is irregular. A radical way of putting it would be to say that there must be a sense in which the irregular is part of the normative. A less radical way, and the way adopted by this thesis, is to say that any account of the normative dimension of social life must not be such as to exclude the importance of irregularity from social life. This will mean 1) not characterising conventions, norms and rules as determinants of appropriateness and inappropriateness; 2) not thinking of them as necessary; 3) not thinking of them as necessarily governing minds; and 4) not thinking of them as necessarily shared.¦-¦L'argument principal de la thèse est que, pour rendre compte de la dimension normative de la vie sociale, il faut veiller à ne pas exclure la perspective de la deuxième personne - une perspective importante pour comprendre la vie sociale et la capacité requise pour y participer.¦Cette perspective nous permet d'imaginer la vie sociale comme un mélange ou un équilibre entre le régulier et l'irrégulier, l'interaction entre des individus pouvant être appréhendée comme l'expérience de chaque personne avec «l'autre» d'une manière qui n'est pas immédiatement compréhensible, et qui ne peut pas, peut-être, être ultimement comprise. Pour participer à la vie sociale, l'on doit avoir la capacité de rester hésitant et «réactif» dans ses relations avec les autres, de rester ouvert à leur altérité et de tolérer l'ambiguïté, l'incertitude et l'imprévisibilité des interactions sociales.¦Adopter une perspective «à la deuxième personne» conduit à une autre manière de penser la normativité en général, et la dimension normative de la vie sociale en particulier. Cela ne veut pas dire qu'il faut abandonner la distinction entre le normatif et le régulier - une distinction qui garde une importance fondamentale - mais qu'il faut reconnaître l'irrégulier comme faisant partie de la vie sociale et comme étant digne, en tant que tel, d'être expliqué. Une conception radicale pourrait même concevoir l'irrégulier comme faisant partie intégrante de la normativité. Une approche moins radicale, qui est celle adoptée dans cette thèse, est de dire que tout compte-rendu de la dimension normative de la vie sociale doit prendre en considération l'importance de l'irrégularité dans la vie sociale. Une telle approche implique que les conventions, normes et règles (1) ne déterminent pas ce qui est approprié ou inapproprié; (2) ne sont pas toujours nécessaires ; (3) ne gouvernent pas le fonctionnement de l'esprit ; et (4) ne sont pas nécessairement partagées.

Peri-insular hemispherotomy: potential pitfalls and avoidance of complications.

Techniques for cerebral hemispherectomy have progressively evolved towards more disconnection and less excision over the last 50 years. Peri-insular hemispherotomy (PIH), as described by the senior author, has the maximal ratio of disconnection to excision among all procedures for hemispheric epilepsy. In this study, we focus on surgical complications and intraoperative anatomical observations during PIH over the last 10 years. Based on this experience, the procedure has undergone some modifications, which we detail herein.

Prolonged antiretroviral therapy initiated at seroconversion is associated with a polyfunctional HIV-1-specific T-cell profile comparable to that of long-term non-progressors (LTNPs)

Background: Early initiation of antiretroviral therapy (ART) may dramatically curtail cumulative immunological damage allowing maximal levels of immune preservation/reconstitution and induce an immunovirological status similar to that of HIV-1 LTNPs with low viral reservoirs and polyfunctional HIV-1 specific T cell responses.Methods: We performed a cross-sectional study of an HIV-1 seroconverter cohort on long-term ART (LTTS) and compared it to one of LTNPs. Inclusion criteria for 20 LTTS were: (a) ?4 years ART; (b) long-term aviremia and (c) absence of treatment failure and for 15 LTNPs: (a) ?7 years of documented HIV-1 infection; (b) <1000 HIV-1 RNA copies/mL and ?500 CD4+ T-cells/mm3 in >90% of measurements; (d) absence of AIDS-defining conditions; (e) ART-naı¨ve except for temporary ART for prevention of MTCT. In both cohorts, we analysed residual viral replication and reservoirs in peripheral blood, as measured by cellassociated HIV-1 RNA and DNA in PBMCs, respectively and used polychromatic flow cytometry to analyse HIV-1-specific CD4+ and CD8+ T-cell functional profile in terms of cytokine production using IFN-c, IL-2, TNF-a production.Results: Cell-associated DNA [47.7 (4.8-583.2) in LTTS and 19.7 (0.5-295.5) in LTNPS, p=0.10], and RNA [3.9 (0-36) and 5.8 (0-10.3), respectively] were shown to be similarly low in both cohorts. We identified 103 CD8 T cell epitope-specific responses, all subjects responding to ?1 epitope. Mean responding number of responding epitopes per patient was 2 and 4 in LTTS and LTNPS, respectively. Mean% of cytokine-secreting CD8 T cells was 0.37% and 0.50% (p=0.06), of these 43% and 39% (p=0.12) were secreting simultaneously IFN-c, IL-2 and TNF-a. Respective values for CD4 T cells were 0.28% and 0.33% (p=0.28) of which 33% and 30% (0.32) were secreting these 3 cytokines simultaneously.Conclusions: Long-term aviremia after very early ART initiation is associated with low levels of reservoirs saturation ad residual replication. Although less broad CD8 T cell responses were found in LTTS, HIV-1 specific CD4 and CD8 T cell responses showed similar magnitude and functional profile in the 2 cohorts. Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs. (BHIVA Research Award Winner 2008: Anna Garcia-Diaz.)

Reducing the learning curve for the treatment of morphoeic (sclerosing) basal cell carcinoma of the face.

The treatment of morphoeic (or sclerosing) basal cell carcinoma (mBCC) of the face is associated with high rates of incomplete excision and recurrence. A principal risk factor for incomplete resection is the grade of surgeon. We did a prospective, randomised study of 40 consecutive patients with mBCC of the face. The extent of the tumour was assessed under standard conditions by consultant surgeons and compared with assessments by resident surgeons with the help of the Varioscope, a combination of microscope and loupe glasses with strong illumination and a maximal magnification of 7x. The data from a former retrospective study of all excisions of mBCC of the face during a five-year period at the hospital served as control. Residents with the support of the Varioscope achieved a rate of incomplete excisions similar to that of consultants under standard conditions. There was a significant reduction of the rate of incomplete resections by resident surgeons thanks to high magnification and good lighting (p=0.02). High magnification and good lighting were useful in learning how to recognise skin changes associated with mBCC of the face and achieving a low rate of incomplete excisions.

Language and syntactic impairment following stroke in late bilingual aphasics.

PURPOSE: Bilingual aphasia generally affects both languages. However, the age of acquisition of the second language (L2) seems to play a role in the anatomo-functional correlation of the syntactical/grammatical processes, thus potentially influencing the L2 syntactic impairment following a stroke. The present study aims to analyze the influence of late age of acquisition of the L2 on syntactic impairment in bilingual aphasic patients. METHODS: Twelve late bilingual participants (speaking French as L2 and either English, German, Italian or Spanish as L1) with stroke-induced aphasia participated in the study. The MAST or BAT aphasia batteries were used to evaluate overall aphasia score. An auditory syntactic judgement task was developed and used to test participants syntactic performance. RESULTS: The overall aphasia scores did not differ between L1 and L2. In a multiple case analysis, only one patient had lower scores in L2. However, four patients presented significantly lower performances in syntactic processing in the late L2 than in their native language (L1). In these four patients the infarct was localized, either exclusively or at least partially, in the pre-rolandic region. CONCLUSION: This pilot study suggests that, in late bilingual aphasics, syntactic judgment abilities may be more severely impaired in L2, and that this syntactic deficit is most likely to occur following anterior lesions.

Oxygen-sensing reporter strain of Pseudomonas fluorescens for monitoring the distribution of low-oxygen habitats in soil.

The root-colonizing bacterium Pseudomonas fluorescens CHA0 was used to construct an oxygen-responsive biosensor. An anaerobically inducible promoter of Pseudomonas aeruginosa, which depends on the FNR (fumarate and nitrate reductase regulation)-like transcriptional regulator ANR (anaerobic regulation of arginine deiminase and nitrate reductase pathways), was fused to the structural lacZ gene of Escherichia coli. By inserting the reporter fusion into the chromosomal attTn7 site of P. fluorescens CHA0 by using a mini-Tn7 transposon, the reporter strain, CHA900, was obtained. Grown in glutamate-yeast extract medium in an oxystat at defined oxygen levels, the biosensor CHA900 responded to a decrease in oxygen concentration from 210 x 10(2) Pa to 2 x 10(2) Pa of O(2) by a nearly 100-fold increase in beta-galactosidase activity. Half-maximal induction of the reporter occurred at about 5 x 10(2) Pa. This dose response closely resembles that found for E. coli promoters which are activated by the FNR protein. In a carbon-free buffer or in bulk soil, the biosensor CHA900 still responded to a decrease in oxygen concentration, although here induction was about 10 times lower and the low oxygen response was gradually lost within 3 days. Introduced into a barley-soil microcosm, the biosensor could report decreasing oxygen concentrations in the rhizosphere for a 6-day period. When the water content in the microcosm was raised from 60% to 85% of field capacity, expression of the reporter gene was elevated about twofold above a basal level after 2 days of incubation, suggesting that a water content of 85% caused mild anoxia. Increased compaction of the soil was shown to have a faster and more dramatic effect on the expression of the oxygen reporter than soil water content alone, indicating that factors other than the water-filled pore space influenced the oxygen status of the soil. These experiments illustrate the utility of the biosensor for detecting low oxygen concentrations in the rhizosphere and other soil habitats.

Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient.

BACKGROUND: Missense mutations in three different genes encoding amyloid-β precursor protein, presenilin 1 and presenilin 2 are recognized to cause familial early-onset Alzheimer disease. Also duplications of the amyloid precursor protein gene have been shown to cause the disease. At the Dept. of Geriatric Medicine, Karolinska University Hospital, Sweden, patients are referred for mutation screening for the identification of nucleotide variations and for determining copy-number of the APP locus. METHODS: We combined the method of microsatellite marker genotyping with a quantitative real-time PCR analysis to detect duplications in patients with Alzheimer disease. RESULTS: In 22 DNA samples from individuals diagnosed with clinical Alzheimer disease, we identified one patient carrying a duplication on chromosome 21 which included the APP locus. Further mapping of the chromosomal region by array-comparative genome hybridization showed that the duplication spanned a maximal region of 1.09 Mb. CONCLUSIONS: This is the first report of an APP duplication in a Swedish Alzheimer patient and describes the use of quantitative real-time PCR as a tool for determining copy-number of the APP locus.

X-ray microtomography of Larger Foraminifera

X-ray microtomography has become a new tool in earth sciences to obtain non-destructive 3D-image data from geological objects in which variations in mineralogy, chemical composition and/or porosity create sufficient x-ray density contrasts.We present here first, preliminary results of an application to the external and internal morphology of Permian to Recent Larger Foraminifera. We use a SkyScan-1072 high-resolution desk-top micro-CT system. The system has a conical x-ray source with a spot size of about 5µm that runs at 20-100kV, 0-250µA, resulting in a maximal resolution of 5µm. X-ray transmission images are captured by a scintillator coupled via fibre optics to a 1024x1024 pixel 12-bit CCD. The object is placed between the x-ray source and the scintillator on a stub that rotates 360°around its vertical axis in steps as small as 0.24 degrees. Sample size is limited to 2 cm due to the absorption of geologic material for x-rays. The transmission images are back projected using a Feldkamp algorithm into a vertical stack of up to 1000 1Kx1K images that represent horizontal cuts of the object. This calculation takes 2 to several hours on a Double-Processor 2.4GHz PC. The stack of images (.bmp) can be visualized with any 3D-imaging software, used to produce cuts of Larger Foraminifera. Among other applications, the 3D-imaging software furnished by SkyScan can produce 3D-models by defining a threshold density value to distinguish "solid" from "void. Several models with variable threshold values and colors can be imbricated, rotated and cut together. The best results were obtained with microfossils devoid of chamber-filling cements (Permian, Eocene, Recent). However, even slight differences in cement mineralogy/composition can result in surprisingly good x-ray density contrasts.X-ray microtomography may develop into a powerful tool for larger microfossils with a complex internal structure, because it is non-destructive, requires no preparation of the specimens, and produces a true 3D-image data set. We will use these data sets in the future to produce cuts in any direction to compare them with arbitrary cuts of complex microfossils in thin sections. Many groups of benthic and planktonic foraminifera may become more easily determinable in thin section by this way.

PchC thioesterase optimizes nonribosomal biosynthesis of the peptide siderophore pyochelin in Pseudomonas aeruginosa.

In Pseudomonas aeruginosa, the antibiotic dihydroaeruginoate (Dha) and the siderophore pyochelin are produced from salicylate and cysteine by a thiotemplate mechanism involving the peptide synthetases PchE and PchF. A thioesterase encoded by the pchC gene was found to be necessary for maximal production of both Dha and pyochelin, but it was not required for Dha release from PchE and could not replace the thioesterase function specified by the C-terminal domain of PchF. In vitro, 2-aminobutyrate, a cysteine analog, was adenylated by purified PchE and PchF proteins. In vivo, this analog strongly interfered with Dha and pyochelin formation in a pchC deletion mutant but affected production of these metabolites only slightly in the wild type. Exogenously supplied cysteine overcame the negative effect of a pchC mutation to a large extent, whereas addition of salicylate did not. These data are in agreement with a role for PchC as an editing enzyme that removes wrongly charged molecules from the peptidyl carrier protein domains of PchE and PchF.

High-density electric source imaging (esi) in focal epilepsy: a prospective study of 150 operated patients

Purpose: EEG is mandatory in the diagnosis of the epilepsy syndrome. However, its potential as imaging tool is still under estimated. In the present study, we aim to determine the prerequisites of maximal benefit of electric source imaging (ESI) to localize the irritative zone in patients with focal epilepsy. Methods: One hundred fifty patients suffering from focal epilepsy and with minimum 1 year postoperative follow-up were studied prospectively and blinded to the underlying diagnosis. We evaluated the influence of two important factors on sensitivity and specificity of ESI: the number of electrodes (low resolution, LR-ESI: <30 versus high resolution, HR-ESI: 128-256 electrodes), and the use of individual MRI (i-MRI) versus template MRI (t-MRI) as the head model. Findings: ESI had a sensitivity of 85% and a specificity of 87% when HR-ESI with i-MRI was used. Using LR-ESI, sensitivity decreased to 68%, or even 57% when only t-MRI was available. The sensitivity of HR-ESI/i-MRI compared favorably with those of MRI (76%), PET (69%) and ictal/interictal SPECT (64%). Interpretation: This study on a large patient group shows excellent sensitivity and specificity of ESI if 128 EEG channels or more are used for ESI and if the results are coregistered to the patient's individual MRI. Localization precision is as high as or even higher than established brain imagery techniques. HR-ESI appears to be a valuable additional imaging tool, given that larger electrode arrays are easily and rapidly applied with modern EEG equipment and that structural MRI is nearly always available for these patients.

Association between social relationships and survival of Swiss octogenarians. A five-year prospective, population-based study.

BACKGROUND AND AIMS: Data from the literature reveal the contrasting influences of family members and friends on the survival of old adults. On one hand, numerous studies have reported a positive association between social relationships and survival. On the other, ties with children may be associated with an increased risk of disability, whereas ties with friends or other relatives tend to improve survival. A five-year prospective, population-based study of 295 Swiss octogenarians tested the hypothesis that having a spouse, siblings or close friends, and regular contacts with relatives or friends are associated with longer survival, even at a very old age. METHODS: Data were collected through individual interviews, and a Cox regression model was applied to assess the effects of kinship and friendship networks on survival, after adjusting for socio-demographic and health-related variables. RESULTS: Our analyses indicate that the presence of a spouse in the household is not significantly related to survival, whereas the presence of siblings at baseline improves the oldest old's chances of surviving five years later. Moreover, the existence of close friends is a central component in the patterns of social relationships of oldest adults, and one which is significantly associated with survival. Overall, the protective effect of social relationships on survival is more related to the quality of those relationships (close friends) than to the frequency of relationships (regular contacts). CONCLUSIONS: We hypothesize that the existence of siblings or close friends may beneficially affect survival, due to the potential influence on the attitudes of octogenarians regarding health practices and adaptive strategies.

Clinical and hormonal effects of the new angiotensin II receptor antagonist LRB081.

The renin-angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. Antagonizing angiotensin (Ang) II at the receptor site may produce fewer side effects than inhibition of the promiscuous converting enzyme. The present study was designed to assess in healthy human subjects the effect of LRB081, a new orally active AT1-receptor antagonist, on the pressor action of exogenous Ang II. At the same time, plasma hormones and drug levels were monitored. At 1-week intervals and in a double-blind randomized fashion, 8 male volunteers received three doses of LRB081 (10, 40, and 80 mg) and placebo. Blood pressure (BP) was measured at a finger by photoplethysmograph. The peak BP response to intravenous injection of a standard dose of Ang II was determined before and for < or = 24 h after administration of an oral dose of LRB081 or placebo. After drug administration, the blood BP response to Ang II was expressed in percent of the response before drug administration. At the same time, plasma renin activity (PRA), Ang II, aldosterone, catecholamine (radioassays), and drug levels (by high-performance liquid chromatography) were monitored. After LRB081 administration, a dose dependent inhibition of the BP response to Ang II was observed. Maximal inhibition of the systolic BP response was 54 +/- 3 (mean +/- SEM), 63 +/- 2, and 93 +/- 1% with 10, 40, and 80 mg LRB081, respectively. The time to peak was 3 h for 6 subjects and 4 and 6 h for 2 others. Preliminary plasma half-life (t1/2) was calculated at 2 h. With the highest dose, the inhibition remained significant for 24 h (31 +/- 5%, p < 0.05). Maximal BP-blocking effect and maximal plasma drug level coincided, suggesting that the unmetabolized LRB081 is responsible for the antagonistic effect. PRA and Ang II increased dose dependently after LRB081 intake. Aldosterone, epinephrine, and norepinephrine concentrations remained unchanged. No clinically significant adverse reaction was observed during the study. LRB081 is a well-tolerated, orally active, potent, and long-acting Ang II receptor antagonist. Unlike in the case of losartan, no active metabolite of LRB081 has been shown to be responsible for the main effects.

Local Competition, Inbreeding, and the Evolution of Sex-Biased Dispersal.

Using game theory, we developed a kin-selection model to investigate the consequences of local competition and inbreeding depression on the evolution of natal dispersal. Mating systems have the potential to favor strong sex biases in dispersal because sex differences in potential reproductive success affect the balance between local resource competition and local mate competition. No bias is expected when local competition equally affects males and females, as happens in monogamous systems and also in polygynous or promiscuous ones as long as female fitness is limited by extrinsic factors (breeding resources). In contrast, a male-biased dispersal is predicted when local mate competition exceeds local resource competition, as happens under polygyny/promiscuity when female fitness is limited by intrinsic factors (maximal rate of processing resources rather than resources themselves). This bias is reinforced by among-sex interactions: female philopatry enhances breeding opportunities for related males, while male dispersal decreases the chances that related females will inbreed. These results meet empirical patterns in mammals: polygynous/promiscuous species usually display a male-biased dispersal, while both sexes disperse in monogamous species. A parallel is drawn with sex-ratio theory, which also predicts biases toward the sex that suffers less from local competition. Optimal sex ratios and optimal sex-specific dispersal show mutual dependence, which argues for the development of coevolution models.

Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester.

OBJECTIVE: To investigate the influence of obesity on the regulation of myocardial glucose metabolism following protein kinase C (PKC) activation in obese (fa/fa) and lean (Fa/?) Zucker rats. DESIGN: Isolated hearts obtained from 17-week-old lean and obese Zucker rats were perfused with 200 nM phorbol 12-myristate 13-acetate (PMA) for different time periods prior to the evaluation of PKC and GLUT-4 translocation. For metabolic studies isolated hearts from 48 h starved Zucker rats were perfused with an erythrocytes-enriched buffer containing increased concentrations (10-100 nM) of PMA. MEASUREMENTS: Immunodetectable PKC isozymes and GLUT-4 were determined by Western blots. Glucose oxidation and glycolysis were evaluated by measuring the myocardial release of 14CO2 and 3H2O from [U-14C]glucose and [5-3H]glucose, respectively. RESULTS: PMA (200 nM) induced maximal translocation of ventricular PKCalpha from the cytosol to the membranes within 10 min. This translocation was 2-fold lower in the heart from obese rats when compared to lean rats. PMA also induced a significant translocation of ventricular GLUT-4 from the microsomal to the sarcolemmal fraction within 60 min in lean but not in obese rats. Rates of basal cardiac glucose oxidation and glycolysis in obese rats were approximately 2-fold lower than those of lean rats. Perfusion with increasing concentrations of PMA (10-100 nM) led to a significant decrease of cardiac glucose oxidation in lean but not in obese rats. CONCLUSION: Our results show that in the heart of the genetically obese Zucker rat, the impairment in PKCalpha activation is in line with a diminished activation of GLUT-4 as well as with the lack of PMA effect on glucose oxidation.

Epidermal growth factor (EGF) stimulation of cultured brain cells. I. Enhancement of the developmental increase in glial enzymatic activity.

Serum-free aggregating cell cultures of fetal rat telencephalon grown in the presence of 3 ng/ml (5 X 10(-10) M) epidermal growth factor (EGF) until day 12 showed 2- to 3-fold increased activities in the two glial enzymes, glutamine synthetase (GLU-S) and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase). This effect was concentration-dependent, with maximal stimulation in cultures treated daily with 3 ng/ml EGF. Addition of EGF during the first 10 culture days was sufficient to produce a maximal stimulation of both GLU-S and CNPase on day 19, whereas treatments starting on day 12 were ineffective. The stimulation of GLU-S preceded that of CNPase. The EGF-induced increase in GLU-S activity was not directly dependent on the presence of insulin, triiodothyronine, or hydrocortisone in the medium, whereas insulin was required for the stimulation of CNPase. A single dose of 5 ng/ml EGF on day 2 caused a slight but significant decrease in DNA synthesis after day 6. The present results indicate that in serum-free aggregating cell cultures of fetal rat telencephalon EGF partially inhibits DNA synthesis, and stimulates an early step in glial differentiation.