Multipotentiality of skin-derived precursors: application to the regeneration of skin and other tissues.

Skin-derived precursors (SKPs) have been described as multipotent dermal precursors. Here, we provide a review of the breadth and depth of scientific literature and studies regarding SKPs, accounting for a large number of scientific publications. Interestingly, these progenitors can be isolated from embryonic and adult skin, as well as from a population of dermal cells cultured in vitro in monolayer. Gathering information from different authors, this review explores different aspects of the SKP theme, such as the potential distinct origins of SKPs in rodents and in humans, and also their ability to differentiate in vitro and in vivo into multiple lineages of different progeny. This remarkable capacity makes SKPs an interesting endogenous source of precursors to explore in the framework of experimental and therapeutic applications in different domains. SKPs are not only involved in the skin's dermal maintenance and support as well as wound healing, but also in hair follicle morphogenesis. This review points out the interests of future researches on SKPs for innovative perspectives that may be helpful in many different types of scientific and medical domains.

Les cellules souches précurseurs dérivées de la peau (nommées SKPs) ont été décrites comme des progéniteurs dermiques multipotents. La présente revue permet d'avoir une vue d'ensemble des études et travaux portant sur le thème des SKPs, regroupant un nombre important de publications scientifiques. Il est intéressant de noter que ces cellules progénitrices peuvent être isolées de la peau embryonnaire et adulte, ainsi que d'une population de cellules dermiques cultivées in vitro en monocouche. Réunissant les travaux de plusieurs auteurs, cette revue explore différents thèmes autour des SKPs, tels que leur origine chez les rongeurs et chez l'homme ; mais aussi, leur capacité à se différencier in vitro et in vivo en un grand nombre de lignées cellulaires de descendances différentes. Cette capacité fondamentale des SKPs en fait une source de précurseurs endogènes intéressante à explorer dans le cadre d'applications expérimentales et thérapeutiques dans différents domaines. Les SKPs participent non seulement à l'homéostasie, au maintien du derme, mais aussi à la cicatrisation des plaies et à la morphogenèse du follicule pileux. Cette revue souligne l'intérêt des expérimentations en cours et à venir concernant les SKPs en vue de perspectives innovantes pouvant influencer la recherche dans de nombreux domaines scientifiques et médicaux.

Does providing the correct diagnosis as feedback after self-explanation improve medical students diagnostic performance?

BACKGROUND: Self-explanation without feedback has been shown to improve medical students' diagnostic reasoning. While feedback is generally seen as beneficial for learning, available evidence of the value of its combination with self-explanation is conflicting. This study investigated the effect on medical students' diagnostic performance of adding immediate or delayed content-feedback to self-explanation while solving cases. METHODS: Ninety-four 3rd-year students from a Canadian medical school were randomly assigned to three experimental conditions (immediate-feedback, delayed-feedback, control). In the learning phase, all students solved four clinical cases by giving i) the most likely diagnosis, ii) two main arguments supporting this diagnosis, and iii) two plausible alternative diagnoses, while using self-explanation. The immediate-feedback group was given the correct diagnosis after each case; delayed-feedback group received the correct diagnoses only after the four cases; control group received no feedback. One week later, all students solved four near-transfer (i.e., same final diagnosis as the learning cases but different scenarios) and four far-transfer cases (i.e., different final diagnosis from the learning cases and different scenarios) by answering the same three questions. Students' diagnostic accuracy (score for the response to the first question only) and diagnostic performance (combined score of responses to the three questions) scores were assessed in each phase. Four one-way ANOVAs were performed on each of the two scores for near and far-transfer cases. RESULTS: There was a significant effect of experimental condition on diagnostic accuracy on near-transfer cases (p < .05). The immediate-feedback and delayed-feedback groups performed equally well, both better than control (respectively, mean = 90.73, standard deviation =10.69; mean = 89.92, standard deviation = 13.85; mean = 82.03, standard deviation = 17.66). The experimental conditions did not significantly differ on far-transfer cases. CONCLUSIONS: Providing feedback to students in the form of the correct diagnosis after using self-explanation with clinical cases is potentially beneficial to improve their diagnostic accuracy but this effect is limited to similar cases. Further studies should explore how more elaborated feedback combined with self-explanation may impact students' diagnostic performance on different cases.

Surveillance of systemic autoimmune rheumatic diseases using administrative data.

There is growing interest in developing tools and methods for the surveillance of chronic rheumatic diseases, using existing resources such as administrative health databases. To illustrate how this might work, we used population-based administrative data to estimate and compare the prevalence of systemic autoimmune rheumatic diseases (SARDs) across three Canadian provinces, assessing for regional differences and the effects of demographic factors. Cases of SARDs (systemic lupus erythematosus, scleroderma, primary Sjogren's, polymyositis/dermatomyositis) were ascertained from provincial physician billing and hospitalization data. We combined information from three case definitions, using hierarchical Bayesian latent class regression models that account for the imperfect nature of each case definition. Using methods that account for the imperfect nature of both billing and hospitalization databases, we estimated the over-all prevalence of SARDs to be approximately 2-3 cases per 1,000 residents. Stratified prevalence estimates suggested similar demographic trends across provinces (i.e. greater prevalence in females-versus-males, and in persons of older age). The prevalence in older females approached or exceeded 1 in 100, which may reflect the high burden of primary Sjogren's syndrome in this group. Adjusting for demographics, there was a greater prevalence in urban-versus-rural settings. In our work, prevalence estimates had good face validity and provided useful information about potential regional and demographic variations. Our results suggest that surveillance of some rheumatic diseases using administrative data may indeed be feasible. Our work highlights the usefulness of using multiple data sources, adjusting for the error in each.

Mandible changes evaluated by computed tomography following Botulinum Toxin A injections in square-faced patients.

BACKGROUND: A facial contour that is oval is more pleasing in Asian women. Patients with a square face often seek facial contouring procedures to improve their appearance. Treatment often involves various combinations of Botulinum NeuroToxin A (BoNTA) injections into the masseters and/or mandibular angle resection. Many physicians claim that muscle paralysis with injections alone will decrease pulling on the underlying bone and also treat underlying bony flaring when present. Muscular changes after BoNTA injections have been well documented. However, the effect of BoNTA injections on the underlying mandibular bone morphology has not been studied to the best of the authors' knowledge. The goal of this study was to determine whether there are mandibular changes after masseter injection with botulinum toxin. METHODS: In this retrospective study of ten female patients seeking treatment for a square face, three-dimensional CT scans were taken before and 3 months after standardized BoNTA injections in bilateral masseters. Mandibular cortex thickness, mandibular bone thickness, and mandibular volume were measured. RESULTS: Soft-tissue changes were observed but no bony changes were observed 3 months after injections. CONCLUSIONS: In this study of adult patients, there were no statistically significant mandibular changes 3 months after BoNTA injection. The current theory of mandibular flaring resolution after partial muscle paralysis is not supported by our findings. Therefore, a patient presenting both masseteric hypertrophy and bony flaring will most likely require a combined muscular and bony procedure.

Microarray profiling of gene expression in human keratinocytes suggests a new protective activity against UV-induced DNA damage for a compound previously known to interact with SCF-KIT signalling pathway.

The stem cell factor (SCF) and its protein-tyrosine kinase receptor KIT are together implicated in the regulation of diverse biological processes and particularly in melanogenesis. Indeed, this signalling pathway controls melanoblast migration from the neural crest during embryogenesis and allows the communication between keratinocytes and melanocytes in the adult. In melanocytes, the binding of SCF to its transmembrane receptor leads to the activation of signalling pathways implicating protein kinases which finally control the expression of pigmentation-related genes. We have developed a biological compound called IV09.007, which we previously described as a modulator of the SCF/KIT signalling pathway with a pro-pigmenting effect. In the present work, we have studied the expression and localization of both SCF and KIT mRNAs and proteins in the skin or skin-derived cell lines. Then, we explored with a microarray approach the ability of IV09.007 to modulate the expression of genes in human keratinocytes and melanocytes in culture. Thereby, we observed the regulation of genes implicated in DNA repair, mainly related to base/nucleotides excision pathways. A modulated transcriptional response was also observed for some genes implicated in the response against oxidative stress, in apoptosis inhibition and in lowering inflammatory immune response. These microarray results predicted a conferred protective effect of IV09.007 and we verified this hypothesis by performing comet assays on UVB-irradiated keratinocytes or melanocytes, to demonstrate the efficacy of IV09.007 on preventing DNA damage.

Laboratory safety evaluation of bedinvetmab, a canine anti-nerve growth factor monoclonal antibody, in dogs.

Nerve growth factor (NGF), a critical mediator of nociception, is a novel analgesic therapeutic target. Bedinvetmab, a canine monoclonal antibody (mAb), binds NGF and inhibits its interaction with tropomyosin receptor kinase A (trkA) and p75 neurotrophin receptor (p75NTR) receptors. The objective of three integrated laboratory studies was to demonstrate the safety of bedinvetmab in adult laboratory Beagle dogs. Daily health, veterinary, clinical pathology, systemic exposure, and anti-drug antibody evaluations were performed. Study 1 additionally included electrocardiography, neurologic, and ophthalmic assessments, and radiographic monitoring of joints of the appendicular skeleton. Study 2 evaluated T-lymphocyte-dependent immune function. Study 3 evaluated the safety of short-term concurrent administration of carprofen, a nonsteroidal anti-inflammatory drug (NSAID), with bedinvetmab. Studies 1 and 3 included terminal pathology and histopathology evaluations. Study designs and procedures included directed complementary morphologic and functional evaluations of a literature- and in vitro-based list of potential safety issues related to the NGF signaling pathway and characteristics engineered into this mAb. Screening-level general procedures evaluated effects associated with mAbs that target and inhibit soluble agonist cytokines. There were no treatment-related adverse changes in clinical evaluations, clinical neurological and ophthalmic examinations, joints, immune morphology or function, and no effects of short-term concurrent NSAID usage. Treatment-emergent immunogenicity was not observed. Bedinvetmab (1 mg/kg SC monthly; 3× and 10× dose multiples) was well tolerated in normal laboratory Beagle dogs for 6 months and with 2 weeks' concurrent NSAID administration.

Alveolar bone grafting in the treatment of midline alveolar cleft and diastema in incomplete median cleft lip.

Median cleft lip is a rare congenital anomaly. The wide diastema with mesial tipping observed in these patients has been largely overlooked. A midline submucosal alveolar cleft prevents adequate treatment. The purpose of this article is to describe an alveolar bone grafting (ABG) technique used in the combined surgical-orthodontic approach to diastema treatment in patients presenting with incomplete median cleft lip. Patients treated for incomplete median cleft lip and diastema were identified in the clinic registry from 1981 to 2007. Six patients were identified; 4 underwent ABG before permanent maxillary incisor eruption, the other 2 were seen later when they were 11 years old. All 6 ABGs were successful. The incisors erupted through the graft or were successfully moved into it with lasting results. Follow-up ranged from 8 to 21 years. The existence of a midline submucosal alveolar cleft and subsequent diastema should be recognized and addressed in all patients who present with incomplete median cleft lip repair. This includes taking maxillary occlusal view X-rays before the age of 5 years to detect the cleft, and proceed to ABG if necessary, generally before permanent maxillary incisor eruption.

Sealing one's fate: control of cell death in neurons.

BCL-2 family members and caspases are essential components of the death machinery in neurons. Identification of Apaf-1 as the mammalian homologue of Caenorhabditis elegans ced-4 provided the final proof of the complete conservation of the C. elegans programmed cell death pathway in mammals. When neurons are deprived of trophic factors, a sequence of events is initiated, which includes a reduction in macromolecule synthesis, elevation of c-Jun and cyclin D1, and activation of BAX. The final episode of this sequence is the activation of caspases, which may mark the death commitment point at which neurons cannot be rescued by addition of trophic factors. In addition, recent evidence suggests that the components in the developmental programmed cell death pathway may play a critical role in neurodegenerative disorders.

Caspase-2 deficiency prevents programmed germ cell death resulting from cytokine insufficiency but not meiotic defects caused by loss of ataxia telangiectasia-mutated (Atm) gene function.

It is well established that programmed cell death claims up to two-thirds of the oocytes produced during gametogenesis in the developing fetal ovaries. However, the mechanisms underlying prenatal germ cell loss in females remain poorly understood. Herein we report that caspase-11 null female mice are born with a reduced number of oocyte-containing primordial follicles. This phenotype is likely due to failed cytokine processing known to occur in caspase-11 mutants since neonatal female mice lacking both interleukin (IL)-1alpha and IL-1beta also exhibit a reduced endowment of primordial follicles. In addition, germ cell death in wild-type fetal ovaries cultured ex vivo is suppressed by either cytokine, likely via ligand activation of type 1 IL-1 receptors expressed in fetal germ cells. Normal oocyte endowment can be restored in caspase-11 null female mice by simultaneous inactivation of the gene encoding the cell death executioner enzyme, caspase-2. However, caspase-2 deficiency cannot overcome gametogenic failure resulting from meiotic recombination defects in ataxia telangiectasia-mutated (Atm) null female mice. Thus, genetically distinct mechanisms exist for developmental deletion of oocytes via programmed cell death, one of which probably functions as a meiotic quality-control checkpoint that cannot be overridden.

Characterization of the avian Ich-1 cDNA and expression of Ich-1L mRNA in the hen ovary.

We have sequenced the chicken interleukin-1beta-converting enzyme (ICE) and ced-3 homolog (Ich-1) cDNA, and evaluated Ich-1 mRNA expression in the hen ovary during follicle development. While two alternatively spliced forms of Ich-1, Ich-1L and Ich-1S, were amplified by PCR from an embryonic chicken cDNA library, only the Ich-1L form was found to be expressed in adult ovarian granulosa and theca tissues. The deduced amino acid (aa) sequence of ICH-1L is 70.8% identical to human ICH-1L and contains the conserved QACRG peptide active catalytic sequence characteristic of many ICE-related family of cysteine proteases.

Dopamine D2 receptor binding in adrenal medulla: characterization using [3H]spiperone.

The possibility that dopamine may function as a neuromodulator or neurotransmitter in the adrenal gland, and not merely serve as a precursor to the catecholamines, has been suggested. If this hypothesis is correct, receptors for dopamine should be identifiable in the adrenal. The present work demonstrates the existence of a high-affinity receptor in adrenal medulla using [3H]spiperone as the radioligand to label the receptors. [3H]Spiperone bound rapidly, reversibly, and with high affinity to bovine adrenal medullary membranes. Scatchard analysis yielded a Kd of 0.09 nM and a Bmax of 51 fmol/mg protein. In competition binding experiments, dopaminergic antagonists were at least 100 times more potent in displacing [3H]spiperone from its binding sites than adrenergic or serotonergic receptor antagonists. Similarly, agonists at the dopamine receptor more readily competed for [3H]spiperone binding than other receptor agonist drugs tested. Furthermore, D2 selective antagonists and agonists were much more potent than D1 receptor ligands. These results suggest that [3H]spiperone may bind to a high-affinity D2 dopamine receptor in adrenal medulla.

The Dominic-R: a pictorial interview for 6- to 11-year-old children.

OBJECTIVE: To review the Dominic-R and the Terry questionnaires, respectively, for white and African-American children, both DSM-III-R-based, and more recent DSM-IV-based computerized versions. METHOD: Five papers describing the development, content, validation studies, and establishment of the diagnostic cutpoints of these instruments are reviewed. The instruments are pictorial, fully structured, and designed to assess mental disorders in children 6 to 11 years of age. Symptom descriptions complement the visual stimulus, providing better information-processing than visual or auditory stimuli alone. Cognitive immaturity of young children bars frequency, duration, and age-of-onset measurements, restricting correspondence with DSM criteria. DSM-IV (computerized versions) and DSM-III-R (paper versions) disorders being assessed include specific (simple) phobias, separation anxiety, generalized anxiety (overanxious), depression/dysthymia, attention-deficit hyperactivity, oppositional defiant, and conduct disorder. RESULTS: Test-retest reliability of symptoms and symptom scores and criterion validity against clinical judgment support the visual-auditory combination of stimuli to assess child mental health. CONCLUSION: Intended for clinical, epidemiological, and screening purposes, these instruments are short and simple. Although it only approximates DSM-III-R and DSM-IV criteria, the pictorial format permits young children to be reliable informants about their mental health.

Do children aged 9 through 11 years understand the DISC Version 2.25 questions?

OBJECTIVE: To assess the understanding of Diagnostic Interview Schedule for Children-Version 2.25 (DISC-2.25) questions by children aged 9 through 11 years. METHOD: Two hundred forty children were recruited from four public schools. The cognitive appraisal of 280 questions from the most prevalent DSM-III-R diagnoses was evaluated. The collaboration of four children was necessary to cover one DISC. Sixty DISCs, evenly distributed according to age and sex, were completed. Two child psychiatrists evaluated the children's answers. Nonparametric tests were used to assess understanding of questions as a whole, of time concepts (overall, categories, number), and of questions based on the number of words. RESULTS: Children aged 9, 10, and 11 years understood 38%, 38%, and 42% of the questions as a whole, respectively, and 26%, 24%, and 30% of the overall time concepts, respectively. The understanding rates of questions as a whole were significantly higher than those of overall time concepts. Durations were significantly better understood than periods and frequencies, and questions having one time component were significantly better grasped than those with two or more. Shorter questions were significantly better understood than longer ones. CONCLUSION: Although the DISC has been greatly improved since the initial version, the results suggest that additional revision is needed before clinicians or researchers use the DISC with younger children.

Diagnostic Interview Schedule for Children (DISC-2.25) in Quebec: reliability findings in light of the MECA study.

OBJECTIVE: To examine the reliability of the French Diagnostic Interview Schedule for Children (DISC-2.25) in Quebec in light of other DISC-2 studies conducted in the National Institute of Mental Health's Methods for the Epidemiology of Child and Adolescent Mental Disorders Study. METHOD: Reliability was assessed for DSM-III-R disorders in a community sample comprising 260 parents of youths aged 6 to 14 years and 145 adolescents aged 12 to 14 years. The DISC was completed at home. The mean test-retest interval was 13.8 days for parents and 12.8 days for adolescents. RESULTS: Parents' reports: Internal consistency was acceptable for a majority of disorders. The kappa coefficients were in the fair or good ranges except for depressive disorders and were higher for children than for adolescents, and intraclass correlations were higher than kappa coefficients. Adolescents' reports: Internal consistency was acceptable or nearly acceptable for a majority of disorders. The kappa coefficients were in the fair range, and intraclass correlations were higher than kappa coefficients. The kappa coefficients were significantly higher for the test-retest interval of 7 to 14 days than for 14 to 21 days for adolescents' reports of anxious disorders and internalizing disorders. CONCLUSION: The French DISC-2.25 shows acceptable internal consistency and fair to good test-retest reliability. Across DISC-2 studies, test-retest reliability of the parents' reports improved for anxiety and depressive disorders. Among sources of variation, studies on attributes of questions would be meaningful.

[Inaccuracy of serum albumin measurements in renal failure patients using a dye-binding method (author's transl)]. / Insuffisance renale et interference dans le dosage de l'albumine serique par une methode de liaison de colorant

A survey of serum albumin determinations in a group of patients with renal failure revealed that albumin reasurements using the 2-(4'-hydroxyphenylazo)-benzoic acid (HABA) dye-binding method were understimated when compared to results obtained with the biuret method. Equilibrium dialysis of the HABA dye binding to albumin are reported. Scatchard plot analysis showed that an average of 5.7 binding sits per molecule of albumin were unavailable in renal failure patients. The binding interference encountered in these patients indicates that alubumin measurements using dye binding techniques should not be used for these patients.

A structured pictorial questionnaire to assess DSM-III-R-based diagnoses in children (6-11 years): development, validity, and reliability.

This paper presents a structured pictorial instrument, the Dominic questionnaire, to assess mental disorders in 6- to 11-year-old children. Ninety-nine drawings represent situations corresponding to DSM-III-R based ADHD, CD, ODD, MDD, SAD, OAD, and SPh. However, cognitive limitation of 6- to 11-year-old children do not allow for time-related measurement. The instrument takes 15-20 min to administer. Reliability and validity of the Dominic questionnaire were studied in Parent DISC-2 positive and negative outpatient and general population samples and against clinical judgement. The pictorial approach provides acceptable test-retest reliability and the instrument makes standardized assessment possible for children as young as 6 years of age.

Correlates of mental disorders in the Quebec general population of 6 to 14-year olds.

Previous epidemiological studies of correlates of child and adolescent mental disorders in the general population have focused more on child/adolescent and socioeconomic/sociodemographic characteristics than on family characteristics. Moreover, there are no generally accepted methods to analyze and interpret correlates. The purpose of the Quebec Child Mental Health Survey in this regard was twofold: (1) to identify correlates of DSM-III-R internalizing and externalizing disorders according to informant (youth, parent, teacher), for three age groups (6-8, 9-11, and 12-14 years), including relevant family characteristics not considered in previous studies; and (2) to interpret the relative importance of risk indicators by ranking correlates according to strength and consistency of association across age groups. Logistic regression models suggest the inconsistency of correlates across informants. The ranking of correlates reveals that individual and family characteristics make a more important contribution than do socioeconomic characteristics, thereby supporting the relevance of proximal variables in the development of psychopathology.

[Dextropropoxyphene hepatotoxicity: four cases and literature review]. / Dextropropoxyphène et atteintes hépatiques: à propos de 4 cas et revue de littérature.

We report 4 cases of hepatic injury in patients treated with a dextropropoxyphene-paracetamol combination in which the causal relationship with dextropropoxyphene can be suspected. These four cases show similarities with the 29 cases found in international publications. Hepatotoxicity occurs more frequently among old patients and women. Clinically, this condition can mimic a biliary tract disease with sometimes few or no symptoms. Biochemical criteria can show cholestatic, mixed or cytolytic hepatitis. Intrahepatic cholestasis may be found in liver biopsies sometimes suggesting cholangitis. Outcome is favourable on withdrawal of the drug. The mechanism of action of dextropropoxyphene is discussed.

[Suicidal ideation and behavior of young college students in Montréal.]. / Le mal de vivre : comportements et idéations suicidaires chez les cégépiens de Montréal.

Suicide among youth is a subject of growing concern. Successful suicides, however, represent only a slight part of the total problem. A study conducted with 666 francophones students attending four C.E.G.E.P. in the Montreal territory reveals that 21.2 % of them say that they have already experienced serious suicidal ideation. 12.2 % have had these experiences within the last twelve months. There are also 3.6 % of the students who admitted to having attempted suicide during the same period, and 8.1 % during their lifetime. More than half of the students say they also have experienced suicidal obsessions such as a fear or a desire to throw themselves in front of the metro. Parental separation and poor health represent the two most serious risk factors. Nearly three quarters of the people who have had serious suicidal thoughts have thought of plans or have confided them to members of their social circle... The reaction of the milieu was reported as positive in only half the cases. Clinical interviews with 25 of the respondents showed that the suicidal ideation reported, corresponded, in almost all cases, with a period of great anguish. The fact of thinking of suicide did have, on the other hand, some positive effects in producing awareness of the possibility of a control over one's destiny.

A minimum data set of animal health laboratory data to allow for collation and analysis across jurisdictions for the purpose of surveillance.

A minimum data set consisting of 15 data elements originating from laboratory submissions and results was formulated by a national committee of epidemiologists in Canada for the purposes of disease reporting, disease detection and analysis. The data set consists of both data that are filled out on the submission form as well as the results of the laboratory testing. The elements in the data set are unique identifier, premises identification, date submitted, geographic location, species, farm type, group type, total population of tested species on the farm, number sick, number dead, test(s) performed, disease agent, test result, disease classification by submitter and final laboratory diagnosis. The data set was designed to be concise while allowing for domestic and international disease reporting, effective analysis, including geographic, temporal and prevalence outputs, and syndromic surveillance to enable disease detection. The selected data elements do not identify the producer as specific geographic and nominal information is not included in the data set. The data elements selected, thus, allow for voluntary collaboration and data sharing by avoiding issues associated with privacy legislation.