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Biomedical subjects

B A Bernard

Publications and source records attributed to B A Bernard.

At least 19 recordsLinked to original sources
PubMed2006

Effect of donepezil on motor and cognitive function in Huntington disease.

Striatal cholinergic dysfunction may be important in Huntington disease (HD). We studied whether donepezil improves chorea, cognition, and quality of life (QoL) in HD. Thirty patients were randomly assigned to treatment with donepezil or placebo. At the doses studied, donepezil did not improve chorea, cognition, or QoL. Adverse events were similar between both groups. Based on this small sample study, donepezil was not an effective treatment for HD.

Chorea↗
PubMed2005

Human hair shape is programmed from the bulb.

BACKGROUND: Few biological data on curly hair follicles have been reported in the literature. OBJECTIVES: To investigate the growth and morphology of curly hair follicles. METHODS: Follicles were dissected from scalp skin samples from African, Guyanese and caucasian volunteers and were observed macroscopically, in culture in William's E medium, and by immunohistochemistry. RESULTS: Macroscopic study of scalp biopsies obtained from African volunteers showed that the dermal implantation of follicles was curved with a retrocurvature at the level of the bulb, as opposed to a straight shape in caucasian follicles. The bulb itself was bent, in the shape of a golf club, while both the outer root sheath (ORS) and the connective tissue sheath were dissymmetrical along the follicle. In vitro growth of curly hair follicles was slightly slower than that of caucasian follicles but, more importantly, the curvature was maintained in the hair shaft produced in vitro. As shown by immunohistochemistry, the proliferative matrix compartment of curly hair follicles was asymmetrical, Ki-67-labelled cells being more numerous on the convex side and extending above the Auber line. On the convex part of the follicle, the ORS was thinner and the differentiation programmes of the inner root sheath and hair shaft were delayed. Furthermore, some ORS cells expressed alpha-smooth muscle actin protein on the concave side of the curvature, reflecting a mechanical stress. CONCLUSIONS: Hair curliness is programmed from the bulb and is linked to asymmetry in differentiation programmes.

Biopsy↗
PubMed2004

Human hair greying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath.

BACKGROUND: Although hair greying is a very common phenomenon characterized by loss of pigment in the hair shaft, the events that cause and control natural hair whitening with age in humans are still unclear. OBJECTIVES: To decipher the origin of natural hair whitening. METHODS: Human hair melanocytes were immunohistochemically characterized at different stages of whitening. RESULTS: Loss of hair shaft melanin was found to be associated with a decrease in both bulb melanin content and bulb melanocyte population. Although few melanocytes were present in the bulbs of grey hair, they still expressed tyrosinase and tyrosinase-related protein-1, synthesized and transferred melanins to cortical keratinocytes as seen by the presence of melanin granules. In white hair bulbs, no melanocytes could be detected either with pMel-17 or vimentin labelling. Pigmented hair follicles are known to contain inactive melanocytes in the outer root sheath (ORS), and grey and white hairs were also found to contain some of these quiescent melanocytes. However, their population was decreased compared with pigmented hair follicles, ranging from small to nil. This depletion of melanocytes in the different areas of white hairs was detected throughout the hair cycle, namely at telogen and early anagen stages. In contrast, the infundibulum and sebaceous gland of both pigmented and white hairs showed a similar distribution of melanocytes. Furthermore, other distinct cell populations located in the ORS, namely putative stem cells, Merkel cells and Langerhans cells were equivalently identified in pigmented and white hairs. CONCLUSIONS: Thus, hair greying appears to be a consequence of an overall and specific depletion of bulb and ORS melanocytes of human hair.

Adult↗
PubMed2003

Hair keratin pattern in human hair follicles grown in vitro.

The keratin family includes epithelial (soft) keratins and hair (hard) keratins, and can be divided into acidic type I and basic to neutral type II subfamilies. Recently, nine type I and six type II hair keratin genes have been characterized through the screening of a human PAC library. The expression of these genes in the hair follicle was determined in vivo and a combined catalog of acidic and basic hair keratins was established. In this study, we investigated the expression and localization of most of the human hair keratin members of both types in human hair grown in vitro. We show that in vitro growth of hair follicles for 10 days in complete William's E culture medium did not alter the expression pattern of hair keratins. Similarly to the in vivo situation, each hair keratin was localized in precise and discrete compartments of the follicle, ranging from the matrix to the upper cortex and/or the hair cuticle. This study shows that the increase in length of in vitro grown follicles was accompanied by the proper hair shaft keratinization process. It also shows that hair follicle integrity was maintained in vitro, both in terms of gross morphology and molecular organization despite the complexity of the keratin expression pattern.

Culture Techniques↗
PubMed2002

The follicular automaton model: effect of stochasticity and of synchronization of hair cycles.

Human scalp hair consists of a set of about 10(5)follicles which progress independently through developmental cycles. Each hair follicle successively goes through the anagen (A), catagen (C), telogen (T) and latency (L) phases that correspond, respectively, to growth, arrest and hair shedding before a new anagen phase is initiated. Long-term experimental observations in a group of ten male, alopecic and non-alopecic volunteers allowed determination of the characteristics of hair follicle cycles. On the basis of these observations, we previously proposed a follicular automaton model to simulate the dynamics of human hair cycles and the development of different patterns of alopecia [Halloy et al. (2000) Proc. Natl Acad. Sci. U.S.A.97, 8328-8333]. The automaton model is defined by a set of rules that govern the stochastic transitions of each follicle between the successive states A, T, L and the subsequent return to A. These transitions occur independently for each follicle, after time intervals given stochastically by a distribution characterized by a mean and a standard deviation. The follicular automaton model was shown to account both for the dynamical transitions observed in a single follicle, and for the behaviour of an ensemble of independently cycling follicles. Here, we extend these results and investigate additional properties of the model. We present a deterministic version of the follicular automaton. We show that numerical simulations of the stochastic version of the automaton yield steady-state level of follicles in the different phases which approach the levels predicted by the deterministic equations as the number of follicles progressively increases. Only the stochastic version can successfully reproduce the fluctuations of the fractions of follicles in each of the three phases, observed in small follicle populations. When the standard deviation is reduced or when the follicles become otherwise synchronized, e.g. by a periodic external signal inducing the transition of anagen follicles into telogen phase, large-amplitude oscillations occur in the fractions of follicles in the three phases. These oscillations are not observed in humans but are reminiscent of the phenomenon of moulting observed in a number of mammalian species.

Alopecia↗
PubMed2002

What is the 'true' function of skin?

Conventional textbook wisdom portrays the skin as an organ that literally enwraps whatever each of us stands for as a more or less functional, individual member of the mammalian species, and has it that the skin primarily establishes, controls and transmits contacts with the external world. In addition, the skin has long been recognized to protect the organism from deleterious environmental impacts (physical, chemical,microbiological), and is well-known as crucial for the maintenance of temperature, electrolyte and fluid balance. Now, ever more studies are being published that show the skin to also operate as a huge and highly active biofactory for the synthesis,processing and/or metabolism of an astounding range of e.g. structural proteins, glycans, lipids and signaling molecules. Increasingly, it becomes appreciated that the skin, furthermore, is an integral component of the immune, nervous and endocrine systems, with numerous lines of cross-talk between these systems established intracutaneously (e.g. Ann NY Acad Sci Vol 885, 1999; Endocrine Rev 21:457-487, 2000; Physiol Rev 80:980-1020, 2001; Exp Dermatol 10: 349-367, 2001). All these emerging cutaneous functions beyond the classical image of the skin as a barrier and sensory organ are immediately relevant for many of the quandaries that clinical dermatology, dermatopathology, and dermatopharmacology are still struggling with to-date, and offer the practising dermatologist attractive new targets for therapeutic intervention. Yet, many of these skin functions are not even mentioned in dermatology textbooks and await systematic therapeutic targeting. Following a suggestion by Enno Christophers, the current 'Controversies' feature brings together an unusually diverse council of biologists and clinicians, who share their thought-provoking views with the readers and allow us to peek into the future of research in cutaneous biology, not the least by reminding us of the -- often ignored -- evolutionary and embryonal origins of our favorite organ. Hopefully, this unique discussion feature will foster an understanding of the 'true' skin functions that is both more comprehensive and more profound than conventional teaching on this topic, and will stimulate more than 'skin-deep' reflections on the full range of skin functions.

Aging↗
PubMed2002

Type-1 steroid 5 alpha-reductase is functionally active in the hair follicle as evidenced by new selective inhibitors of either type-1 or type-2 human steroid 5 alpha-reductase.

Steroid 5 alpha-reductase catalyzes the reduction of testosterone (T) into the very potent androgen dihydrotestosterone (DHT). The different tissue expression patterns of the two isoforms of 5 alpha-reductase, namely type-1 and type-2 5 alpha-reductase (5 alpha-R1 and 5 alpha-R2, respectively), have prompted studies directed towards the synthesis of selective 5 alpha-R1 or 5 alpha-R2 inhibitors. In this present work, we have performed a structure/activity study on the inhibitory potential of indole carboxylic acids against hair follicle 5 alpha-reductase activity. We have demonstrated that this class of molecules were potent inhibitors of either 5 alpha-R1 or 5 alpha-R2 or both depending on (i) substituents in positions 4, 5 or 6 and (ii) the presence of a free carboxylic group. We have also found that only 5 alpha-R1 or 5 alpha-R1/R2 inhibitors were able to inhibit 5 alpha-reductase activity in plucked hairs from female volunteers or in freshly isolated female hair follicles, selective 5 alpha-R2 inhibitors being inactive.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2001

Identification of clustered cells in human hair follicle responsible for MMP-9 gelatinolytic activity: consequences for the regulation of hair growth.

BACKGROUND: The control of human hair follicle growth and differentiation is dependent upon several well-identified factors, including androgens, cytokines, and growth factors. In humans, alopecia androgenetica is a common aging process thought to be regulated through complex genetic imbalances, which also involve several of these crucial identified factors (and probably others not yet characterized), alone or in combination. Among these factors, epidermal growth factor (EGF), as well as pro-inflammatory cytokines, play a pivotal role, as evidenced by their direct inhibitory effects on hair growth both in vitro and in vivo. Following such treatments, the in vitro growth of hair follicles was rapidly arrested and deleterious modifications of hair morphology were also observed. AIM: Because these cytokines act, at least partly, through the induction of matrix metalloproteinases (MMP), and because tissue remodeling occurs during the hair cycle, we attempted to identify and localize MMP in the human pilosebaceous unit. METHOD: We used zymography to observe human hair follicles in culture in vitro. RESULTS: We observed that human hair follicles in culture in vitro mainly and almost exclusively produce MMP-2 and MMP-9 gelatinolytic activities. Furthermore, after stimulation with EGF, tumor necrosis factor-alpha (TNF-alpha), or interleukin-1alpha (IL-1alpha), MMP-9 production was strongly increased. Using immunohistochemistry, we then precisely localized MMP-9 in the lower part of the inner root sheath (Henle's layer) of control human anagen hair follicles. CONCLUSIONS: Cytokine- and EGF-induced upregulation of MMP-9 in the lower epithelial compartment of the human hair bulb is a major mechanism through which hair follicle involution, observed in alopecia, may occur.

Cells, Cultured↗
PubMed2001

Hair diameter diversity: a clinical sign reflecting the follicle miniaturization.

BACKGROUND: The degree of androgenetic alopecia is generally evaluated either by global clinical scales or time-consuming methods like phototrichogram or histological studies. We describe a new clinical and reliable scoring method based on hair diameter diversity. OBSERVATIONS: (1) The clinical macroscopic scoring we propose for hair density was significantly correlated with Hamilton classification and with histological hair density. (2) Diversity in hair diameter was the main and most accurate clinical parameter linked to follicle miniaturization. (C) The anagen-telogen ratio decreased in parallel with the decrease in clinical hair density score. CONCLUSIONS: Considering that hair follicle miniaturization is the key point during androgenic alopecia onset and development, diversity in hair diameter represents an important feature to consider as an accurate clinical sign reflecting hair follicle miniaturization. Moreover, diversity in hair diameter seems to be an easily accessible and reliable parameter that should be taken into consideration for further characterization of hair disorders. By itself, we believe that this clinical feature constitutes a new tool of substantial help for the diagnosis and management of androgenic alopecia.

Adult↗
PubMed2000

Modeling the dynamics of human hair cycles by a follicular automaton.

The hair follicle cycle successively goes through the anagen, catagen, telogen, and latency phases, which correspond, respectively, to hair growth, arrest, shedding, and absence before a new anagen phase is initiated. Experimental observations collected over a period of 14 years in a group of 10 male volunteers, alopecic and nonalopecic, allowed us to determine the characteristics of scalp hair follicle cycles. On the basis of these observations, we propose a follicular automaton model to simulate the dynamics of human hair cycles. The automaton model is defined by a set of rules that govern the stochastic transitions of each follicle between the successive states anagen, telogen, and latency, and the subsequent return to anagen. The transitions occur independently for each follicle, after time intervals given stochastically by a distribution characterized by a mean and a variance. The follicular automaton model accounts both for the dynamical transitions observed in a single follicle and for the behavior of an ensemble of independently cycling follicles. Thus, the model successfully reproduces the evolution of the fractions of follicle populations in each of the three phases, which fluctuate around steady-state or slowly drifting values. We apply the follicular automaton model to the study of spatial patterns of follicular growth that result from a spatially heterogeneous distribution of parameters such as the mean duration of anagen phase. When considering that follicles die or miniaturize after going through a critical number of successive cycles, the model can reproduce the evolution to hair patterns similar to well known types of diffuse or androgenetic alopecia.

Alopecia↗
PubMed2000

Melanocyte subpopulation turnover during the human hair cycle: an immunohistochemical study.

The human hair cycle is characterized by successive phases of growth and involution that imply tissue regression and regeneration. As a consequence, the hair melanin unit has to be renewed in a cyclic manner. Actually, the behavior of human hair follicle melanocytes throughout the hair cycle has been poorly studied. Thus, the origin of melanocytes present in the bulb after human hair regeneration is still not clarified, and neither are the events that control the melanin biosynthesis activity in the human hair bulb. In this study, we showed at the cellular level that in human pigmented hair follicles, the expression of tyrosinase and tyrosinase-related protein-1 (TRP-1) was detectable during the anagen phases III/IV through VI, only in those melanocytes which were located in the bulb. During the catagen phase, the two evaluated melanogenic enzymes were detectable no more, although melanocytes were still present in the preceding bulbar area. The epithelial column of catagen follicles and the capsule of telogen follicles also contained inactive melanocytes as evidenced by pMel-17 labeling. At the induction of a new anagen hair follicle, some melanocytes were committed to cell division, but only when located in the nascent bulb close to the dermal papilla. Our results emphasize the close relationship between melanogenesis and the hair cycle and suggest that in humans, melanogenesis is restricted to anagen hair follicles not because of the regulation of tyrosinase activity, but because of melanogenic enzyme expression, e.g., tyrosinase and TRP-1. Furthermore, the fact that in the newly developing anagen hair follicles, cell-division commitment and tyrosinase and TRP-1 expression were observed in melanocytes only when located in the nascent bulb suggests a highly regio-specific melanocyte stimulation in early the anagen phase.

Cell Division↗
PubMed2000

Thyroid hormone receptor beta1 is expressed in the human hair follicle.

To understand better the mechanisms by which thyroid hormone can exert its effects on the hair follicle, we looked for the expression of members of the thyroid hormone receptor (TR) family in human hair follicles. Immunoreactive TRs were detected in both dermal and epithelial compartments of the human pilosebaceous unit. Using reverse transcriptase-polymerase chain reaction, we established that TRbeta1 was the predominant form of TR expressed in the human hair follicle. In addition, we investigated the effects of 3,3', 5-triiodo-L-thyronine (T3) on the survival of human hair follicles in vitro, to understand the role of this thyroid hormone on hair follicle homeostasis. A physiological level of free T3 significantly enhanced human hair survival in vitro.

Gene Expression↗
PubMed2000

The human hair follicle contains two distinct K19 positive compartments in the outer root sheath: a unifying hypothesis for stem cell reservoir?

Up to now, the localization of stem cells in human anagen hair follicle relied on three complementary approaches; namely, detection of slow cycling cells, detection of high colony forming cells, and differential immunohistochemical staining. These techniques, however, gave conflicting results since stem cells were localized either as long label retaining cells in the so-called bulge area or as high colony forming cells in the lower third of the follicle. In the present study we investigated the expression of cytokeratin 19, a marker for putative stem cell-containing epithelial compartments, in order to characterize stem cell distribution in the human hair follicle throughout the hair cycle. We found that anagen human hair follicles contain two distinct reservoirs for stem cells located in the upper and lower thirds of the follicle. These two reservoirs fuse during the catagentelogen transition phase and individualize again in the newly forming anagen hair follicle.

Biomarkers↗
PubMed1999

Genomic organization and promoter characterization of two human UHS keratin genes.

TTD is a rare human genetic disease caused by mutations in XPB and XPD, two subunits of the transcription/repair factor TFIIH, and whose outstanding clinical characteristic is a lack of most human UHS proteins resulting in sulfur-deficient brittle hair. In an attempt to understand this transcription defect, we report here the genomic cloning of two highly related UHS keratin genes specifically expressed in follicular and epidermal cells. In addition to a high degree of nucleotide homology (87%), both genes also have a similar 90-nt promoter sequence. In-vivo and in-vitro studies allowed us to specify the position of the start sites, the TATA-boxes and some regulatory regions. Results indicate that both genes present common features in the regulation of their transcription and suggest that control of their expression might be affected by mutations in TFIIH subunits.

Amino Acid Sequence↗
PubMed1997

The distribution of alpha 2 beta 1, alpha 3 beta 1 and alpha 6 beta 4 integrins identifies distinct subpopulations of basal keratinocytes in the outer root sheath of the human anagen hair follicle.

The human hair follicle is composed of different concentric compartments, which reflect different programmes of differentiation. Using monoclonal antibodies against alpha 2 beta 1 and alpha 3 beta 1 integrins we demonstrated a shift in their expression, from a basolateral distribution in the basal cells of the lower outer root sheath, to an apicolateral expression in the upper outer root sheath, as in epidermis. This shift takes place in a transition zone, localized to the midpart of the follicle. The distinct basolateral distribution of alpha 2 beta 1 and alpha 3 beta 1 integrins in the lower portion of the outer root sheath coincides with the presence of basal cell protrusions and is probably linked to the presence of the vitreous membrane which surrounds the bottom part of the anagen human hair follicle. Moreover, we showed that the expression of alpha 6 beta 4 integrin is discontinuous along the hair follicle and coincides with that of laminin 5. Together these results establish that within a given compartment-namely the outer root sheath-several domains can be clearly identified, which probably reflect the onset of successive differentiation pathways along the hair follicle.

Antigens, Surface↗
PubMed1997

Activation of cytoprotective prostaglandin synthase-1 by minoxidil as a possible explanation for its hair growth-stimulating effect.

Data from the literature indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, piroxicam, or ibuprofen, induce hair loss in vivo. These NSAIDs are well-known inhibitors of both the cytoprotective isoform of prostaglandin endoperoxide synthase-1 (PGHS-1) and of the inducible form (PGHS-2). By immunohistochemical staining, we found that PGHS-1 is the main isoform present in the dermal papilla from normal human hair follicle (either anagen or catagen), whereas PGHS-2 was only faintly and exclusively expressed in anagen dermal papilla. Thus, PGHS-1 might be the primary target of the hair growth-inhibitory effects of NSAIDs. We thus speculated that activation of PGHS-1 might be a mechanism by which minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxyde) stimulates hair growth in vivo. We demonstrate here that minoxidil is a potent activator of purified PGHS-1 (AC50 = 80 microM), as assayed by oxygen consumption and PGE2 production. This activation was also evidenced by increased PGE2 production by BALB/c 3T3 fibroblasts and by human dermal papilla fibroblasts in culture. Our findings suggest that minoxidil and its derivatives may have a cytoprotective activity in vivo and that more potent second-generation hair growth-promoting drugs might be designed, based on this mechanism.

3T3 Cells↗