IL-7/anti-IL-7 mAb complexes restore T cell development and induce homeostatic T Cell expansion without lymphopenia.

IL-7, a member of the common gamma-chain family of cytokines, is essential for B and T lymphocyte development and homeostasis of mature T cell subsets. Thus, naive and memory T cells are both dependent on IL-7 for survival and homeostatic proliferation under lymphopenic conditions. In line with prior findings with IL-2, we show in this study that the biological activity of IL-7 in vivo is greatly increased by association with anti-IL-7 mAb. Under in vivo conditions, IL-7/mAb complexes displayed 50- to 100-fold higher activity than free IL-7 and induced massive expansion of pre-B cells. IL-7/mAb complexes also increased thymopoiesis in normal mice and restored thymopoeisis in IL-7-deficient mice. For mature T cells, IL-7/mAb complexes induced marked homeostatic proliferation of both naive and memory CD4(+) and CD8(+) cell subsets even under normal T cell-replete conditions. Finally, IL-7/mAb complexes were able to enhance the magnitude of the primary response of Ag-specific naive CD8(+) cells. The strong stimulatory activity of IL-7/mAb complexes could be useful for treatment of immunodeficiency and cancer.

Does less frequent routine monitoring of patients on a stable, fully suppressed cART regimen lead to an increased risk of treatment failure?

OBJECTIVE: To investigate whether HIV-infected patients on a stable and fully suppressive combination antiretroviral therapy (cART) regimen could safely be monitored less often than the current recommendations of every 3 months. DESIGN: Two thousand two hundred and forty patients from the EuroSIDA study who maintained a stable and fully suppressed cART regimen for 1 year were included in the analysis. METHODS: Risk of treatment failure, defined by viral rebound, fall in CD4 cell count, development of new AIDS-defining illness, serious opportunistic infection or death, in the 12 months following a year of a stable and fully suppressed regimen was assessed. RESULTS: One hundred thirty-one (6%) patients experienced treatment failure in the 12 months following a year of stable therapy, viral rebound occurred in 99 (4.6%) patients. After 3, 6 and 12 months, patients had a 0.3% [95% confidence interval (CI) 0.1-0.5], 2.2% (95% CI 1.6-2.8) and 6.0% (95% CI 5.0-7.0) risk of treatment failure, respectively. Patients who spent more than 80% of their time on cART with fully suppressed viraemia prior to baseline had a 38% reduced risk of treatment failure, hazard ratio 0.62 (95% CI 0.42-0.90, P = 0.01). CONCLUSION: Patients who have responded well to cART and are on a well tolerated and durably fully suppressive cART regimen have a low chance of experiencing treatment failure in the next 3-6 months. Therefore, in this subgroup of otherwise healthy patients, it maybe reasonable to extend visit intervals to 6 months, with cost and time savings to both the treating clinics and the patients.

Du traitement précoce des sujets à risque aux risques du traitement précoce. Le dilemme de la prévention des troubles psychotiques [From early treatment of psychosis risk to the risks of early intervention: the dilemma of psychosis prevention].

While the development of early psychosis intervention programs have improved outcome of such disorders, primary prevention strategies are still out of reach. The elaboration, over the last 15 years, of scales and criteria to identify populations at high risk for psychosis is a real progress, but their low specificity is still a major obstacle to their use outside of research projects. For this reason, even if "ultra high risk", subjects present with real psychiatric disorders and sometimes significant decrease in functioning level, the fact that only a small proportion will eventually develop full blown psychosis will probably lead to the rejection of a "psychosis risk syndrom" from the future DSM-V classification.

Place du pathologiste dans la prise en charge néoadjuvante des cancers du sein [Neoadjuvant treatment of breast cancer: implications for the pathologist].

These past few years, neoadjuvant strategy has taken an increasing place in the management of breast cancer patients. This strategy is mainly indicated to obtain a tumour bulk regression allowing a breast conserving surgery in patients that otherwise would have undergone mastectomy. Of note, development of new chemotherapy agents and targeted therapies has critically helped in the progress of neoadjuvant strategy as it is currently associated with better pathological response rates. In this context, the pathologist is at the crossroad of this multidisciplinary process. First, he provides on the initial core needle biopsy the tumour pathological characteristics that are critical for the choice of treatment strategy, i.e. histological type, histological grade, proliferative activity (mitotic count and Ki67/MIB1 index labeling), hormone receptor status (oestrogen receptor and progesterone receptor) and HER2 status. Secondly, the pathologist evaluates the pathological response and the status of surgical margins with regards to the residual tumour on the surgical specimen after neoadjuvant treatment. These parameters are important for the management of the patient, since it has been shown that complete pathological response is associated with improved disease free survival. Several grading systems are used to assess the pathological response in breast and axillary lymph nodes. The most frequently used in France are currently the systems described by Sataloff et al. and Chevallier et al. In this review, we detail the different steps involving the pathologist in neoadjuvant setting, with special regards to the quality process and future perspectives such as emerging predictive biomarkers.

N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development.

BACKGROUND: Glutathione (GSH) is the major cellular redox-regulator and antioxidant. Redox-imbalance due to genetically impaired GSH synthesis is among the risk factors for schizophrenia. Here we used a mouse model with chronic GSH deficit induced by knockout (KO) of the key GSH-synthesizing enzyme, glutamate-cysteine ligase modulatory subunit (GCLM).¦METHODS: With high-resolution magnetic resonance spectroscopy at 14.1 T, we determined the neurochemical profile of GCLM-KO, heterozygous, and wild-type mice in anterior cortex throughout development in a longitudinal study design.¦RESULTS: Chronic GSH deficit was accompanied by an elevation of glutamine (Gln), glutamate (Glu), Gln/Glu, N-acetylaspartate, myo-Inositol, lactate, and alanine. Changes were predominantly present at prepubertal ages (postnatal days 20 and 30). Treatment with N-acetylcysteine from gestation on normalized most neurochemical alterations to wild-type level.¦CONCLUSIONS: Changes observed in GCLM-KO anterior cortex, notably the increase in Gln, Glu, and Gln/Glu, were similar to those reported in early schizophrenia, emphasizing the link between redox imbalance and the disease and validating the model. The data also highlight the prepubertal period as a sensitive time for redox-related neurochemical changes and demonstrate beneficial effects of early N-acetylcysteine treatment. Moreover, the data demonstrate the translational value of magnetic resonance spectroscopy to study brain disease in preclinical models.

Infirmier en psychiatrie de liaison : développement de la supervision en milieu somatique [Liaison psychiatry nurse: The development of supervision in somatic medicine].

BACKGROUND: Over the years, somatic care has become increasingly specialized. Furthermore, a rising number of patients requiring somatic care also present with a psychiatric comorbidity. As a consequence, the time and resources needed to care for these patients can interfere with the course of somatic treatment and influence the patient-caregiver relationship. In the light of these observations, the Liaison Psychiatry Unit at the University Hospital in Lausanne (CHUV) has educated its nursing staff in order to strengthen its action within the general care hospital. What has been developed is a reflexive approach through supervision of somatic staff, in order to improve the efficiency of liaison psychiatry interventions with the caregivers in charge of patients. The kind of supervision we have developed is the result of a real partnership with somatic staff. Besides, in order to better understand the complexity of interactions between the two systems involved, the patient's and the caregivers', we use several theoretical references in an integrative manner. PSYCHOANALYTICAL REFERENCE: The psychoanalytical model allows us to better understand the dynamics between the supervisor and the supervised group in order to contain and give meaning to the affects arising in the supervision space. "Containing function" and "transitional phenomena" refer to the experience in which emotions can find a space where they can be taken in and processed in a secure and supportive manner. These concepts, along with that of the "psychic envelope", were initially developed to explain the psychological development of the baby in its early interactions with its mother or its surrogate. In the field of supervision, they allow us to be aware of these complex phenomena and the diverse qualities to which a supervisor needs to resort, such as attention, support and incentive, in order to offer a secure environment. SYSTEMIC REFERENCE: A new perspective of the patient's complexity is revealed by the group's dynamics. The supervisor's attention is mainly focused on the work of affects. However, these are often buried under a defensive shell, serving as a temporary protection, which prevents the caregiver from recognizing his or her own emotions, thereby enhancing the difficulties in the relationship with the patient. Whenever the work of putting emotions into words fail, we use "sculpting", a technique derived from the systemic model. Through the use of this type of analogical language, affects can emerge without constraint or feelings of danger. Through "playing" in that "transitional space", new exchanges appear between group members and allow new behaviors to be conceived. In practice, we ask the supervisee who is presenting a complex situation, to design a spatial representation of his or her understanding of the situation, through the display of characters significant to the situation: the patient, somatic staff members, relatives of the patient, etc. In silence, the supervisee shapes the characters into postures and arranges them in the room. Each sculpted character is identified, named, and positioned, with his or her gaze being set in a specific direction. Finally the sculptor shapes him or herself in his or her own role. When the sculpture is complete and after a few moments of fixation, we ask participants to express themselves about their experience. By means of this physical representation, participants to the sculpture discover perceptions and feelings that were unknown up to then. Hence from this analogical representation a reflection and hypotheses of understanding can arise and be developed within the group. CONCLUSION: Through the use of the concepts of "containing function" and "transitional space" we position ourselves in the scope of the encounter and the dialog. Through the use of the systemic technique of "sculpting" we promote the process of understanding, rather than that of explaining, which would place us in the position of experts. The experience of these encounters has shown us that what we need to focus on is indeed what happens in this transitional space in terms of dynamics and process. The encounter and the sharing of competencies both allow a new understanding of the situation at hand, which has, of course, to be verified in the reality of the patient-caregiver relationship. It is often a source of adjustment for interpersonal skills to recover its containing function in order to enable caregiver to better respond to the patient's needs.

Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy.

PURPOSE: Evidence has accumulated in recent years suggestive of a genetic basis for a susceptibility to the development of radiation injury after cancer radiotherapy. The purpose of this study was to assess whether patients with severe radiation-induced sequelae (RIS; i.e., National Cancer Institute/CTCv3.0 grade, > or =3) display both a low capacity of radiation-induced CD8 lymphocyte apoptosis (RILA) in vitro and possess certain single nucleotide polymorphisms (SNP) located in candidate genes associated with the response of cells to radiation. EXPERIMENTAL DESIGN: DNA was isolated from blood samples obtained from patients (n = 399) included in the Swiss prospective study evaluating the predictive effect of in vitro RILA and RIS. SNPs in the ATM, SOD2, XRCC1, XRCC3, TGFB1, and RAD21 genes were screened in patients who experienced severe RIS (group A, n = 16) and control subjects who did not manifest any evidence of RIS (group B, n = 18). RESULTS: Overall, 13 and 21 patients were found to possess a total of <4 and > or =4 SNPs in the candidate genes. The median (range) RILA in group A was 9.4% (5.3-16.5) and 94% (95% confidence interval, 70-100) of the patients (15 of 16) had > or =4 SNPs. In group B, median (range) RILA was 25.7% (20.2-43.2) and 33% (95% confidence interval, 13-59) of patients (6 of 18) had > or =4 SNPs (P < 0.001). CONCLUSIONS: The results of this study suggest that patients with severe RIS possess 4 or more SNPs in candidate genes and low radiation-induced CD8 lymphocyte apoptosis in vitro.

A prospective development study investigating focal irreversible electroporation in men with localised prostate cancer: Nanoknife Electroporation Ablation Trial (NEAT).

INTRODUCTION: Focal therapy may reduce the toxicity of current radical treatments while maintaining the oncological benefit. Irreversible electroporation (IRE) has been proposed to be tissue selective and so might have favourable characteristics compared to the currently used prostate ablative technologies. The aim of this trial is to determine the adverse events, genito-urinary side effects and early histological outcomes of focal IRE in men with localised prostate cancer. METHODS: This is a single centre prospective development (stage 2a) study following the IDEAL recommendations for evaluating new surgical procedures. Twenty men who have MRI-visible disease localised in the anterior part of the prostate will be recruited. The sample size permits a precision estimate around key functional outcomes. Inclusion criteria include PSA ≤ 15 ng/ml, Gleason score ≤ 4 + 3, stage T2N0M0 and absence of clinically significant disease outside the treatment area. Treatment delivery will be changed in an adaptive iterative manner so as to allow optimisation of the IRE protocol. After focal IRE, men will be followed during 12 months using validated patient reported outcome measures (IPSS, IIEF-15, UCLA-EPIC, EQ-5D, FACT-P, MAX-PC). Early disease control will be evaluated by mpMRI and targeted transperineal biopsy of the treated area at 6 months. DISCUSSION: The NEAT trial will assess the early functional and disease control outcome of focal IRE using an adaptive design. Our protocol can provide guidance for designing an adaptive trial to assess new surgical technologies in the challenging landscape of health technology assessment in prostate cancer treatment.

Les antagonistes des récep- teurs de l'endothéline ont-ils une place dans le traitement de l'hyper- tension artérielle [Do endothelin receptors antagonists have a place in the treatment of arterial hypertension?].

The discovery in 1988 of endothelin, the most potent human endogenous vasoconstrictor, has opened the race to the discovery of a new weapon against arterial hypertension. The development of the endothelin receptors antagonists (ERAs) and the demonstration of their efficacy in preclinical models initially raised a wave of enthusiasm, which was however tempered due to their unfavorable side effect profile. In this article we will review the phases of the development ERAs, and their current and future place as therapeutic tool against arterial hypertension.

Changes of MAP2 phosphorylation during brain development.

The microtubule-associated protein MAP2 is essential for development of early neuronal morphology and maintenance of adult neuronal morphology. Several splice variants exist, MAP2a-d, with a lack of MAP2a in cat brain. MAP2 is widely used as a neuronal marker. In this study we compared five monoclonal antibodies (MAbs) against MAP2. They show differences in the immunocytochemical distribution of MAP2 isoforms during development of the visual cortex and cerebellum of the cat. Local and temporal differences were seen with MAb AP18, an antibody directed against a phosphorylation-dependent epitope near the N-terminal end. In large pyramidal dendrites in visual cortex, the AP18 epitope remained in parts immunoreactive after treatment with alkaline phosphatase. Three MAbs, AP14, MT-01, and MT-02, recognized the central region of the MAP2b molecule, which is not present in MAP2c and 2d, and reacted with phosphorylation-independent epitopes. During the first postnatal week the immunostaining in cerebellum differed between antibodies in that some cellular elements in external and internal granular layers and Purkinje cells were stained to various degrees, whereas at later stages staining patterns were similar. At early stages, antibody MT-02 stained cell bodies and dendrites in cerebral cortex and cerebellum. With progressing maturation, immunoreactivity became restricted to distal parts of apical dendrites of pyramidal cells and was absent from perikarya and finer proximal dendrites in cortex. MT-02 did not stain MAP2 in cerebellum of adult animals. This study demonstrates that the immunocytochemical detection of MAP2 depends on modifications such as phosphorylation and conformational changes of the molecule, and that MAP2 staining patterns differ between MAbs. Phosphorylation and specific conformations in the molecule may be essential for modulating function and molecular stability of MAP2, and monoclonal antibodies against such sites may provide tools for studying the functional role of modifications.

Endovascular treatment of symptomatic intracranial arterial stenosis: six-year experience in a single-center series of 42 consecutive patients with acute and mid-term results.

BACKGROUND: The limitations of the medical management of symptomatic intracranial arterial stenosis encourage the development of new therapeutic strategies such as intracranial stenting. OBJECTIVE: To report and analyze the results of a series of 42 patients treated with 3 different endovascular techniques: isolated angioplasty, balloon-expandable coronary stents, and the Wingspan self-expandable intracranial stent system. METHODS: Forty-two patients presenting with symptomatic intracranial arterial stenosis were treated with one of these techniques. Computed tomography angiography was performed 6 months after the procedure, and the clinical neurological statuses were categorized using the modified Rankin Scale and the National Institutes of Health Stroke Scale. RESULTS: A total of 42 lesions were treated: 9 with isolated angioplasty, 14 with balloon-expandable coronary stents, and 19 with Wingspan self-expandable intracranial stents. The mean patient age was 62.9 years, and the mean arterial diameter stenosis was 73.9%. Technical success was achieved in 97.6% of the patients. The overall incidence of procedural complications was 21.4%, and the postoperative permanent morbidity/mortality rate was 7.1%. There were 3 cases of in-stent thrombosis (1 fatal) and 5 cases of asymptomatic restenosis (11.9%), 3 in the isolated angioplasty group and 2 in the Wingspan self-expandable intracranial stent group (mean follow-up 20.4 months). The rate of restenosis was higher in the angioplasty group (33%) than in the coronary (0%) and Wingspan stent (10.5%) groups. CONCLUSION: Endovascular treatment of symptomatic intracranial stenosis has significant overall morbidity and mortality rates. Nevertheless, the very critical natural history of severe refractory lesions and the relatively favorable postoperative evolution suggest that it should be considered the first alternative strategy in cases in which medical therapy has failed.

Telementoring during endovascular treatment of abdominal aortic aneurysms: a prospective study.

PURPOSE: To explore the use of telementoring for distant teaching and training in endovascular aortic aneurysm repair (EVAR). METHODS: According to a prospectively designed study protocol, 48 patients underwent EVAR: the first 12 patients (group A) were treated at a secondary care center by an experienced interventionist, who was training the local team; a further 12 patients (group B) were operated by the local team at their secondary center with telementoring by the experienced operator from an adjacent suite; and the last 24 patients (group C) were operated by the local team with remote telementoring support from the experienced interventionist at a tertiary care center. Telementoring was performed using 3 video sources; images were transmitted using 4 ISDN lines. EVAR was performed using intravascular ultrasound and simultaneous fluoroscopy to obtain road mapping of the abdominal aorta and its branches, as well as for identifying the origins of the renal arteries, assessing the aortic neck, and monitoring the attachment of the stent-graft proximally and distally. RESULTS: Average duration of telementoring was 2.1 hours during the first 12 patients (group B) and 1.2 hours for the remaining 24 patients (group C). There was no difference in procedural duration (127+/-59 minutes in group A, 120+/-4 minutes in group B, and 119+/-39 minutes in group C; p=0.94) or the mean time spent in the ICU (26+/-15 hours in group A, 22+/-2 hours in group B, and 22+/-11 hours for group C; p=0.95). The length of hospital stay (11+/-4 days in group A, 9+/-4 days in group B, and 7+/-1 days in group C; p=0.002) was significantly different only for group C versus A (p=0.002). Only 1 (8.3%) patient (in group A: EVAR performed by the experienced operator) required conversion to open surgery because of iliac artery rupture. This was the only conversion (and the only death) in the entire study group (1/12 in group A versus 0/36 in groups B + C, p=0.31). CONCLUSIONS: Telementoring for EVAR is feasible and shows promising results. It may serve as a model for development of similar projects for teaching other invasive procedures in cardiovascular medicine.

Cellular mechanisms underlying the regulation of dendritic development by hepatocyte growth factor.

Acquisition of a mature dendritic morphology is critical for neural information processing. In particular, hepatocyte growth factor (HGF) controls dendritic arborization during brain development. However, the cellular mechanisms underlying the effects of HGF on dendritic growth remain elusive. Here, we show that HGF increases dendritic length and branching of rat cortical neurons through activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Activation of MAPK by HGF leads to the rapid and transient phosphorylation of cAMP response element-binding protein (CREB), a key step necessary for the control of dendritic development by HGF. In addition to CREB phosphorylation, regulation of dendritic growth by HGF requires the interaction between CREB and CREB-regulated transcription coactivator 1 (CRTC1), as expression of a mutated form of CREB unable to bind CRTC1 completely abolished the effects of HGF on dendritic morphology. Treatment of cortical neurons with HGF in combination with brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family that regulates dendritic development via similar mechanisms, showed additive effects on MAPK activation, CREB phosphorylation and dendritic growth. Collectively, these results support the conclusion that regulation of cortical dendritic morphology by HGF is mediated by activation of the MAPK pathway, phosphorylation of CREB and interaction of CREB with CRTC1.

Long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in small-for-gestational-age preterm infants.

OBJECTIVE: To investigate the effects of neonatal hypoglycemia on physical growth and neurocognitive function.Study design: A systematic detection of hypoglycemia (<2.6 mmol/L or 47 mg/dL) was carried out in 85 small-for-gestational-age preterm neonates. Prospective serial evaluations of physical growth and psychomotor development were performed. Retrospectively, infants were grouped according to their glycemic status. RESULTS: The incidence of hypoglycemia was 72.9%. Infants with repeated episodes of hypoglycemia had significantly reduced head circumferences and lower scores in specific psychometric tests at 3.5 years of age. Hypoglycemia also caused reduced head circumferences at 18 months and lower psychometric scores at 5 years of age. Infants with moderate recurrent hypoglycemia had lower scores at 3.5 and 5 years of age compared with the group of infants who had 1 single severe hypoglycemic episode. CONCLUSION: Recurrent episodes of hypoglycemia were strongly correlated with persistent neurodevelopmental and physical growth deficits until 5 years of age. Recurrent hypoglycemia also was a more predictable factor for long-term effects than the severity of a single hypoglycemic episode. Therefore repetitive blood glucose monitoring and rapid treatment even for mild hypoglycemia are recommended for small-for-gestational-age infants in the neonatal period.

Official Positions for FRAX® Bone Mineral Density and FRAX® simplification from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

Tools to predict fracture risk are useful for selecting patients for pharmacological therapy in order to reduce fracture risk and redirect limited healthcare resources to those who are most likely to benefit. FRAX® is a World Health Organization fracture risk assessment algorithm for estimating the 10-year probability of hip fracture and major osteoporotic fracture. Effective application of FRAX® in clinical practice requires a thorough understanding of its limitations as well as its utility. For some patients, FRAX® may underestimate or overestimate fracture risk. In order to address some of the common issues encountered with the use of FRAX® for individual patients, the International Society for Clinical Densitometry (ISCD) and International Osteoporosis Foundation (IOF) assigned task forces to review the medical evidence and make recommendations for optimal use of FRAX® in clinical practice. Among the issues addressed were the use of bone mineral density (BMD) measurements at skeletal sites other than the femoral neck, the use of technologies other than dual-energy X-ray absorptiometry, the use of FRAX® without BMD input, the use of FRAX® to monitor treatment, and the addition of the rate of bone loss as a clinical risk factor for FRAX®. The evidence and recommendations were presented to a panel of experts at the Joint ISCD-IOF FRAX® Position Development Conference, resulting in the development of Joint ISCD-IOF Official Positions addressing FRAX®-related issues.