Cancer chronotherapeutics: experimental, theoretical, and clinical aspects.

The circadian timing system controls cell cycle, apoptosis, drug bioactivation, and transport and detoxification mechanisms in healthy tissues. As a consequence, the tolerability of cancer chemotherapy varies up to several folds as a function of circadian timing of drug administration in experimental models. Best antitumor efficacy of single-agent or combination chemotherapy usually corresponds to the delivery of anticancer drugs near their respective times of best tolerability. Mathematical models reveal that such coincidence between chronotolerance and chronoefficacy is best explained by differences in the circadian and cell cycle dynamics of host and cancer cells, especially with regard circadian entrainment and cell cycle variability. In the clinic, a large improvement in tolerability was shown in international randomized trials where cancer patients received the same sinusoidal chronotherapy schedule over 24h as compared to constant-rate infusion or wrongly timed chronotherapy. However, sex, genetic background, and lifestyle were found to influence optimal chronotherapy scheduling. These findings support systems biology approaches to cancer chronotherapeutics. They involve the systematic experimental mapping and modeling of chronopharmacology pathways in synchronized cell cultures and their adjustment to mouse models of both sexes and distinct genetic background, as recently shown for irinotecan. Model-based personalized circadian drug delivery aims at jointly improving tolerability and efficacy of anticancer drugs based on the circadian timing system of individual patients, using dedicated circadian biomarker and drug delivery technologies.

Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe.

Oculo-auriculo-vertebral spectrum is a complex developmental disorder characterised mainly by anomalies of the ear, hemifacial microsomia, epibulbar dermoids and vertebral anomalies. The aetiology is largely unknown, and the epidemiological data are limited and inconsistent. We present the largest population-based epidemiological study to date, using data provided by the large network of congenital anomalies registries in Europe. The study population included infants diagnosed with oculo-auriculo-vertebral spectrum during the 1990-2009 period from 34 registries active in 16 European countries. Of the 355 infants diagnosed with oculo-auriculo-vertebral spectrum, there were 95.8% (340/355) live born, 0.8% (3/355) fetal deaths, 3.4% (12/355) terminations of pregnancy for fetal anomaly and 1.5% (5/340) neonatal deaths. In 18.9%, there was prenatal detection of anomaly/anomalies associated with oculo-auriculo-vertebral spectrum, 69.7% were diagnosed at birth, 3.9% in the first week of life and 6.1% within 1 year of life. Microtia (88.8%), hemifacial microsomia (49.0%) and ear tags (44.4%) were the most frequent anomalies, followed by atresia/stenosis of external auditory canal (25.1%), diverse vertebral (24.3%) and eye (24.3%) anomalies. There was a high rate (69.5%) of associated anomalies of other organs/systems. The most common were congenital heart defects present in 27.8% of patients. The prevalence of oculo-auriculo-vertebral spectrum, defined as microtia/ear anomalies and at least one major characteristic anomaly, was 3.8 per 100,000 births. Twinning, assisted reproductive techniques and maternal pre-pregnancy diabetes were confirmed as risk factors. The high rate of different associated anomalies points to the need of performing an early ultrasound screening in all infants born with this disorder.

Biomechanical concept and clinical outcome of dual mobility cups

La luxation d'une prothèse totale de la hanche est une complication majeure en termes de morbidité pour le patient et des coûts pour le système de santé. Cette complication est retrouvée entre 2 à 3% selon les séries (1-3) pour des prothèses primaires, et beaucoup plus élevée suite à des révisions. Pour remédier à ce problème, des systèmes de prothèses contraintes sont une option, cependant associés à des descellements fréquents entre 10 à 26 % selon les séries (4-6). Ces échecs étant en partie expliqués par une usure rapide des surfaces de frottements due aux fortes contraintes, mais également par les contraintes cupule-os occasionnant des descellements mécaniques (7). Par conséquent, pour augmenter la stabilité, tout en évitant les contraintes sur le couple de frottement, Bousquet développe, en 1976, une prothèse totale de hanche « à double mobilité ». Ce système consiste à combiner deux articulations apparentes, premièrement une tête métallique dans un insert de polyéthylène, articulé lui- même dans la concavité d'une cupule métallique fixée au bassin. En tant que tel, ce système biomécanique réduirait en théorie le risque de luxation. Dès lors, on aperçoit depuis environ 15 ans une augmentation progressive de l'utilisation de ce type d'implants que ce soit comme implant primaire ou secondaire, chez des patients jeunes ou âgés. Cependant, des études in vitro, ont montré que des grandes surfaces de friction sont associées à une augmentation de l'usure du polyéthylène (8). En revanche, les données sur la cinématique et l'usure, in vivo, de ce type d'implant étaient jusqu'alors limitées. Depuis quelques années, un certain nombre d'études cliniques avec un follow up significatif ont été publiées. CONCLUSIONS ET PERSPECTIVES FUTURES La prothèse totale de hanche à double mobilité, développée par Bousquet dans les années 1970, est un concept novateur dans l'arthroplastie totale de hanche. Depuis sa première conception, de nombreuses améliorations ont été adoptées. Cependant, ses effets à long terme sur la survie de l'implant doivent encore être effectué. Certes, des études ont montré un net effet sur la réduction du taux de luxation des prothèses primaires, lors de révision ou après résection tumorale. Toutefois, compte tenu des données limitées à long terme sur le taux d'usure et le descellement aseptique, il convient d'utiliser ce type d'implant avec prudence, en particulier lors d'arthroplastie primaire chez des patients jeunes.

Processus intégratifs et gouvernance clinique dans la psychiatrie institutionnelle [Integration processes and clinical governance in the psychiatric network]

The Swiss Medical Insurance Act (LAMaL) requires the planning of psychiatric care. This necessitates a coordination between the Department of Public Health and the institutional governance. Given the difficulties to draw comparisons between a wide range of systems in a federal country, the Swiss Conference of the State Directors of Health (CDS) proposed as a first step that each canton present some of the key programs they had developed. In the canton Vaud, the implementation of mobile community treatment teams and of an early intervention program for psychosis was chosen. The main challenges faced were to go past traditional divides within the organisation of the Swiss Health system and to conciliate the requirements of public health with the needs of treating teams, in order to promote early intervention in mental health disorders.

Methadone maintenance treatment in the Swiss Canton of Vaud: demographic and clinical data on 1,782 ambulatory patients.

Using data from the Public Health Service, we studied the demographic and clinical characteristics of 1,782 patients enrolled in methadone maintenance treatment (MMT) during 2001 in the Swiss Canton of Vaud, comparing our findings with the results of a previous study from 1976 to 1986. In 2001, most patients (76.9%) were treated in general practice. Mortality is low in this MMT population (1%/year). While patient age and sex profiles were similar to those found in the earlier study, we did observe a substantial increase in the number of patients and the number of practitioners treating MMT patients, probably reflecting the low-threshold governmental policies and the creation of specialized centers. In conclusion, easier access to MMT enhances the number of patients, but new concerns about the quality of management emerge: benzodiazepine as a concomitant prescription; low rates of screening for hepatitis B, C and HIV, and social and psychiatric preoccupations.

Fluoxetine augmentation in citalopram non-responders: pharmacokinetic and clinical consequences.

In an open trial 11 in-patients with a major depressive episode (ICD-10), extensive metabolizers of mephenytoin (CYP2C19) and dextromethorphan (CYP2D6) and who were non-responders to a 3-wk pretreatment with 40 mg/d citalopram (Cit), were co-medicated for 7 wk (days 0-49) with fluoxetine (Fluox) (10 mg/d). Plasma concentrations of S-Cit and R-Cit significantly increased from day 0 (means+/-S.D.: 28+/-9 and 47+/-11 &mgr;g/l, respectively) to day 49 (58+/-12 and 72+/-21 &mgr;g/l, respectively) (p & 0.01 for each comparison), and the S-Cit/R-Cit ratio increased from 0.61+/-0.16 to 0.82+/-0.12 (p & 0.01). Therefore, Fluox increases the pharmacologically more active S-Cit (in comparison with R-Cit) with some stereoselectivity, most probably by inhibition of CYP2D6 and CYP3A4. Eight of the 11 patients showed clinical improvement (reduction > 50% of the MADRS score) and the combined treatment was generally well tolerated.

The French adaptation of the Health of the Nation Outcome Scale for Children and Adolescents Self-Rated Form (F-HoNOSCA-SR): Validation and clinical routine use.

The current study aimed to explore the validity of an adaptation into French of the self-rated form of the Health of the Nation Outcome Scales for Children and Adolescents (F-HoNOSCA-SR) and to test its usefulness in a clinical routine use. One hundred and twenty nine patients, admitted into two inpatient units, were asked to participate in the study. One hundred and seven patients filled out the F-HoNOSCA-SR (for a subsample (N=17): at two occasions, one week apart) and the strengths and difficulties questionnaire (SDQ). In addition, the clinician rated the clinician-rated form of the HoNOSCA (HoNOSCA-CR, N=82). The reliability (assessed with split-half coefficient, item response theory (IRT) models and intraclass correlations (ICC) between the two occasions) revealed that the F-HoNSOCA-SR provides reliable measures. The concurrent validity assessed by correlating the F-HoNOSCA-SR and the SDQ revealed a good convergent validity of the instrument. The relationship analyses between the F-HoNOSCA-SR and the HoNOSCA-CR revealed weak but significant correlations. The comparison between the F-HoNOSCA-SR and the HoNOSCA-CR with paired sample t-tests revealed a higher score for the self-rated version. The F-HoNSOCA-SR was reported to provide reliable measures. In addition, it allows us to measure complementary information when used together with the HoNOSCA-CR.

Experimental and clinical radiofrequency ablation: proposal for standardized description of coagulation size and geometry.

BACKGROUND: Radiofrequency (RF) ablation is used to obtain local control of unresectable tumors in liver, kidney, prostate, and other organs. Accurate data on expected size and geometry of coagulation zones are essential for physicians to prevent collateral damage and local tumor recurrence. The aim of this study was to develop a standardized terminology to describe the size and geometry of these zones for experimental and clinical RF. METHODS: In a first step, the essential geometric parameters to accurately describe the coagulation zones and the spatial relationship between the coagulation zones and the electrodes were defined. In a second step, standard terms were assigned to each parameter. RESULTS: The proposed terms for single-electrode RF ablation include axial diameter, front margin, coagulation center, maximal and minimal radius, maximal and minimal transverse diameter, ellipticity index, and regularity index. In addition a subjective description of the general shape and regularity is recommended. CONCLUSIONS: Adoption of the proposed standardized description method may help to fill in the many gaps in our current knowledge of the size and geometry of RF coagulation zones.

Risk factor impact on blood flow velocities and clinical outcomes of stented cervical and intracranial stenoses: preliminary observations.

OBJECTIVES: The role of angioplasty/stenting procedures, neurointerventionist experience, vascular risk factors, medical treatment and blood flow velocities were analysed to identify possible causes of intra-stent restenosis (ISR) following stenting of cervical and/or intracranial arteries, assuming progressive atherosclerosis to be the shared mechanism in both territories. Patients. 26 cerebrovascular patients subjected to stenting of severe (≥85%) symptomatic or asymptomatic carotid stenoses or moderate-to-severe (≥50%) intracranial or vertebral stenoses were included. METHODS: Clinical, radiological and ultrasonographic follow-up data were analysed retrospectively. RESULTS: Overall, stenting of the internal carotid artery (ICA) induced significant reductions in peak systolic velocities at 2 years (96±31cm/s vs. 358.2±24.9cm/s at baseline). The procedure-related ischemic complications rate was 7.4% (one hemispheric stroke and one TIA). The rate of ISR≤50% was 8% in the ICA at 2 years; was 50% in the common carotid artery (CCA) at 1 year, with concomitant distal ICA stenosis in 75% of CCA stenting, but all ISR were asymptomatic. Patients with ISR of the ICA were significantly younger (56.8±4.5 vs. 71.3±3.6 years, P=0.042) and had significantly more risk factors (5.5±0.9 vs. 3±0.3, P=0.012). No ISR≥70% was detected. CONCLUSIONS: ISR is relatively infrequent and, when present, it is mild and asymptomatic. Restenosis is more frequent in younger patients and those with several risk factors, and it may also be related to stenting of previous carotid endarterectomy.

Dysmegakaryopoiesis predicting response to therapy in acute myeloid leukaemia. A histologic and clinical study

With standard induction therapy between 50 to 85% of patients with Acute Myeloid Leukaemia (AML) achieve Complete Remission (CR). We investigated whether any morphological feature of bone marrow (BM) plastic embedded biopsies could predict failure of therapy. We reviewed BM plastic embedded biopsies from 54 adult patients presenting with untreated AML. The main histologic parameters analysed were cellularity, dysmegakaryopoiesis (DysM), percentage of marrow blasts and fibrosis. CR was obtained in 34 of 49 treated patients (69%). The rate of CR was significantly lower in the group of patients presenting with DysM: CR was achieved in 54% of the 28 treated patients with DysM and in 90% of the 21 treated patients without DysM (p less than 0.02). Patients with DysM had a significantly lower blood count and bone marrow blasts at presentation. Median age was not significantly different in the 2 groups. Cellularity and fibrosis were not predictive. DysM may be the hallmark of an AML subgroup with distinct clinical behaviour and lower rate of CR with conventional therapy. DysM should be carefully looked for on BM marrow biopsies and aspirate from AML patients at diagnosis.

Glutathione deficit in schizophrenia: strategies to increase glutathione levels in " in vitro " and clinical studies

Summary: Decrease in glutathione (GSH) levels was observed in cerebrospinal fluid, prefrontal cortex and post-mortem striatum of schizophrenia patients. Evidences suggest a defect in GSH synthesis at the levels of the rate-limiting synthesizing enzyme, glutamate cysteine ligase (GCL). Indeed, polymorphisms in the gene of the modifier subunit of GCL (GCLM) was shown to be associated with the disease in three different populations, GCLM gene expression is decreaséd in fibroblasts from patients and the increase in GCL activity induced by an oxidative stress is lower in patients' fibroblasts compared to controls. GSH being a major antioxydant and redox regulator, its presence is of high importance for protecting cells against oxidative stress. The aim of the present work was to use various substances to increase GSH levels by diverse strategies. Since the synthesizing enzyme GCL is defective, bypassing this enzyme was the first strategy we used. GSH ethyl ester (GSHEE), a membrane permeable analog of GSH, succeeded in replenishing GSH levels in cultured neurons and astrocytes previously depleted in GSH by L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GCL. GSHEE also abolished dopamine-induced decrease of NMDA-mediated calcium response observed in BSO-treated neurons. y-Glutamylcysteine ethyl ester (GCSE), a membrane permeable analog of the product of GCL, increased GSH levels only in astrocytes. The second strategy was to boost the defective enzyme GCL. While quercetin (flavonoid) could increase GSH levels only in astrocytes, curcumin (polyphenol) and tertbutylhydroquinone (quinone) were successful in both neurons and astrocytes, via an increase in the gene expression of the two subunits of GCL and, consequently, an increase in the activity of the enzyme. However, FK506, an immunosupressant, was unefficient. Treating astrocytes from GCLM KO mice showed that the modulatory subunit is necessary for the action of the substances. Finally, since cysteine is the limiting precursor in the synthesis of GSH, we hypothesized that we could increase GSH levels by providing more of this precursor. N-acetyl-cysteine (NAC), a cysteine donor, was administered to schizophrenia patients, using adouble-blind and cross-over protocol. NAC significantly improved the mismatch negativity (MMN), a component of the auditory evoked potentials, thought to reflect selective current flowing through open, unblocked NMDA channels. Considering that NMDA function is reduced when GSH levels are low, increasing these levels with NAC could improve NMDA function as reflected by the improvement in the generation of the MMN. Résumé: Les taux de glutathion (GSH) dans le liquide céphalo-rachidien, le cortex préfrontal ainsi que le striatum post-mortem de patients schizophrènes, sont diminués. L'enzyme limitante dans la synthèse du GSH, la glutamyl-cysteine ligase (GCL), est défectueuse. En effet, des polymorphismes dans le gène de la sous-unité modulatrice de GCL (GCLM) sont associés à la maladie, l'expression du gène GCLM est diminuée dans les fibroblastes de patients et, lors d'un stress oxidative, l'augmentation de l'activité de GCL est plus faible chez les patients que chez les contrôles. Le GSH étant un important antioxydant et régulateur du status redox, sa présence est primordiale afin de protéger les cellules contre les stress oxydatifs. Au cours du présent travail, une variété de substances ont été utilisées dans le but d'augmenter les taux de GSH. Passer outre l'enzyme de synthèse GCL qui est défectueuse fut la première stratégie utilisée. L'éthylester de GSH (GSHEE), un analogue du GSH qui pénètre la membrane cellulaire, a augmenté les taux de GSH dans des neurones et des astrocytes déficitaires en GSH dû au L-buthionine-(S,R)-sulfoximine (BSO), un inhibiteur du GCL. Dans ces neurones, le GSHEE a aussi aboli la diminution de la réponse NMDA, induite parla dopamine. L'éthyl-ester de y-glutamylcysteine (GCEE), un analogue du produit de la GCL qui pénètre la membrane cellulaire, a augmenté les taux de GSH seulement dans les astrocytes. La seconde stratégie était d'augmenter l'activité de l'enzyme GCL. Tandis que la quercétine (flavonoïde) n'a pu augmenter les taux de GSH que dans les astrocytes, la curcumin (polyphénol) et le tert-butylhydroquinone (quinone) furent efficaces dans les deux types de cellules, via une augmentation de l'expression des gènes des deux sous-unités de GCL et de l'activité de l'enzyme. Le FK506 (immunosupresseur) n' a démontré aucune efficacité. Traiter des astrocytes provenant de souris GCLM KO a permis d'observer que la sous-unité modulatoire est nécessaire à l'action des substances. Enfin, puisque la cysteine est le substrat limitant dans la synthèse du GSH, fournir plus de ce présurseur pourrait augmenter les taux de GSH. Nacétyl-cystéine (NAC), un donneur de cystéine, a été administrée à des schizophrènes, lors d'une étude en double-aveugle et cross-over. NAC a amélioré le mismatch negativity (MMN), un composant des potentials évoqués auditifs, qui reflète le courant circulant via les canaux NMDA. Puisque la fonctionnalité des R-NMDA est diminuée lorsque les taux de GSH sont bas, augmenter ces taux avec NAC pourrait améliorer la fonction des R-NMDA, réflété par une augmentation de l'amplitude du MMN.

Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type.

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.

Tumor heterogeneity and cancer stem cell paradigm: updates in concept, controversies and clinical relevance.

Although tumor heterogeneity is widely accepted, the existence of cancer stem cells (CSCs) and their proposed role in tumor maintenance has always been challenged and remains a matter of debate. Recently, a path-breaking chapter was added to this saga when three independent groups reported the in vivo existence of CSCs in brain, skin and intestinal tumors using lineage-tracing and thus strengthens the CSC concept; even though certain fundamental caveats are always associated with lineage-tracing approach. In principle, the CSC hypothesis proposes that similar to normal stem cells, CSCs maintain self renewal and multilineage differentiation property and are found at the central echelon of cellular hierarchy present within tumors. However, these cells differ from their normal counterpart by maintaining their malignant potential, alteration of genomic integrity, epigenetic identity and the expression of specific surface protein profiles. As CSCs are highly resistant to chemotherapeutics, they are thought to be a crucial factor involved in tumor relapse and superficially appear as the ultimate therapeutic target. However, even that is not the end; further complication is attributed by reports of bidirectional regeneration mechanism for CSCs, one from their self-renewal capability and another from the recently proposed concept of dynamic equilibrium between CSCs and non-CSCs via their interconversion. This phenomenon has currently added a new layer of complexity in understanding the biology of tumor heterogeneity. In-spite of its associated controversies, this area has rapidly emerged as the center of attention for researchers and clinicians, because of the conceptual framework it provides towards devising new therapies.