Terence Kealey

Effects of interleukins, colony‐stimulating factor and tumour necrosis factor on human hair follicle growth in vitro: a possible role for interleukin‐1 and tumour necrosis factor‐α in alopecia areata

The immune system may be involved in the regulation of normal hair follicle growth as well as in the pathogenesis of some hair diseases. Immunomodulatory cytokines not only act as mediators of immunity and inflammation but also regulate cell proliferation and differentiation and. as such, may play an important part in regulating hair growth. We have investigated the effects of a number of interleukins (IL). colony stimulating factors and tumour necrosis factors (TNF) on hair follicle growth in vitro. Dose‐response studies showed that IL‐1α. IL‐1ß and TNF‐o were potent inhibitors of hair follicle growth. The histology of hair follicles maintained with inhibitory doses of IL‐1α. IL‐1ß and TNF‐α showed similar changes in hair follicle morphology, resulting in the formation of dystrophic anagen hair follicles. These changes in histology were characterized by the condensation and distortion of the dermal papilla, marked vacuolation of the hair follicle matrix, abnormal keratinization of the follicle bulb and inner root sheath, disruption of follicular melanocytes and the presence of melanin granules witbin the dermal papilla. Moreover, these changes in hair follicle morphology are similar to those reported in alopecia areata and suggest that IL‐1α, IL‐1ß and TNF‐α may play an important part in the pathophysiology of inflammatory hair disease.

Human hair growth in vitro: a model for the study of hair follicle biology

The factors that regulate hair follicle growth are still poorly understood. In vitro models may be useful in elucidating some aspects of hair follicle biology. We have developed an in vitro human hair growth model that enables us to maintain isolated human hair follicles for up to 10 days, during which time they continue to grow at an in vivo rate producing a keratinised hair fibre. We have shown that epidermal growth factor (EGF) in our system mimics the in vivo depilatory action of EGF in sheep, and suggest that this occurs as a result of EGF stimulating outer root sheath (ORS) cell proliferation which results in the disruption of normal mechanisms of cell-cell interaction in the hair follicle. We identify transforming growth factor-beta (TGF-beta) as a possible negative regulator of hair follicle growth and show that physiological levels of insulin-like growth factor-I (IGF-I) can support the same rates of hair follicle growth as supraphysiological levels of insulin. Furthermore, in the absence of insulin hair follicles show premature entry into a catagen-like state. This is prevented by physiological levels of IGF-I. Finally we demonstrate that the hair follicle is an aerobic glycolytic, glutaminolytic tissue and discuss the possible implications of this metabolism.

More is less. Economists and governments lag decades behind Derek Price's thinking

Economists and governments lag decades behind Derek Prices thinking.

Peroxisome proliferator-activated receptor and farnesoid X receptor ligands differentially regulate sebaceous differentiation in human sebaceous gland organ cultures in vitro

Background  Nuclear hormone receptors are important in the regulation of epidermal differentiation and have been implicated in lipid metabolism. In particular, there is evidence suggesting that the activation of peroxisome proliferator‐activated receptors (PPARs) is an important factor in the regulation of sebocyte lipogenesis.

Modelling the remission of individual acne lesions in vitro.

Summary Background Acne lesions spontaneously remit, but the mechanism of this remission has not been elaborated. It is known, however, that the remission is associated with a de‐differentiation of sebocytes, causing a cessation of sebum secretion specific to that particular pilosebaceous unit. We have previously described the cytokines that will promote in vitro the lesions of acne.

Rat hair follicle growth in vitro.

Pelage hair follicles were isolated by gentle microdissection from 8–12‐day‐old rats, and maintained in supplemented Williams E medium. Length measurements made on freshly isolated hair follicles, and at 24‐h intervals, showed a significant increase in hair follicle length over 48 h, after which time no further significant increase in length was observed. Photomicrographs of maintained follicles showed that this increase in hair follicle length could be attributed to the production of a keratinized hair shaft. Histology and [methyl‐3H] thymidine autoradiography of freshly isolated hair follicles showed the dermal papilla to be elongated, with thymidine uptake located predominantly in the matrix cells of the hair follicle bulb adjacent to the dermal papilla. This pattern remained unaltered for the first 48 h of maintenance, but after 72 h the dermal papilla had rounded into a tight ball of cells, with very little thymidine uptake occurring in the adjacent matrix cells.

Advances in sebaceous gland research: potential new approaches to acne management

Sebaceous gland development and function is regulated by an expanding array of molecules including transcription factors, hormones, retinoids, growth factors, cytokines and nuclear hormone receptors. We have reviewed the literature to present the current understanding of sebaceous gland development and physiology, with particular emphasis on the control of the sebaceous gland and its implications for acne management. Interestingly, retinoids, cytokines and nuclear hormone receptors appear to be promising inhibitors of sebum synthesis, thus offering new approaches to acne management.

The isolation and maintenance of the human pilosebaceous unit

We have previously developed methods for the isolation and maintenance of human sebaceous glands and hair follicles. However, in long‐term culture the maintenance of both is suboptimal. This may be due to a lack of stem cells, which are thought to be located in the bulge area of the hair follicle, and this region is not present in either model. Isolation of the entire pilosebaceous unit would retain this region, and may lead to improved maintenance of both structures. We describe a method for the isolation of viable, individual, pilosebaceous units by microdissection from human scalp face‐lift skin. The viability of isolated pilosebaceous units has been determined by light microscopy, patterns of DNA synthesis by [methyl‐3H] thymidine autoradiography, and lipogenesis by [U‐14C] acetate uptake into lipids.

Prolonged maintenance of human hair follicles in vitro in a serum‐free medium

We have previously reported the in vitro growth of human hair follicles for up to 4 days in a partially defined medium containing serum. We now report the prolonged in vitro growth of isolated human hair follicles for at least 9 days. This was achieved after analysis of the contribution of certain components of the original medium and, by a process of elimination, deriving a completely defined medium supplemented only with antibiotics. l‐glutamine, insulin and hydrocortisone. We have shown, by [methyl‐3H] thymidine autoradiography, that the hair follicles grown in this medium maintain an in vivo pattern of DNA synthesis, and that the gross morphology and histology of these maintained hair follicles remains similar to that of freshly isolated hair follicles. We have also shown that the patterns of keratin synthesis, as determined by [35S] methionine labelling, do not alter with maintenance.

The energy metabolism in the right and left ventricles of human donor hearts across transplantation.

OBJECTIVE Brain death appears to predominantly affect the right ventricle (RV) and right ventricular failure is a common complication of clinical cardiac transplantation. It is not clear to what extent myocardial energy stores are affected in the operative sequence. We aimed to describe the time-dependent variation in high energy phosphate (HEP) metabolism of the two ventricles, and the relationship with endothelial activation and postoperative functional recovery. METHODS Fifty-two human donors had serial biopsies from the RV and the left ventricle (LV) at (1) initial evaluation, (2) after haemodynamic optimisation, (3) end of cold ischaemia, (4) end of warm ischaemia, (5) reperfusion, and (6) at 1 week postoperatively. HEP was measured by chemiluminescence in biopsies 1-5 and adhesion molecules (P-selectin, E-selectin, VCAM-1) and thrombomodulin were analysed by immunohistochemistry in biopsies 5-6. Seventeen donors and five recipients had RV intraoperative pressure-volume recordings by a conductance catheter. Six patients served as live controls. RESULTS Brain death did not affect HEP metabolism quantitatively. There was no difference between the RV and LV at any time point, but significant time-dependent changes were observed. The RV was prone to HEP depletion at retrieval, with ATP/ADP falling from 3.89 to 3.13, but recovered during cold ischaemia. During warm ischaemia the ATP/ADP ratio fell by approximately 50%, from 5.48 for the RV and 4.26 for the LV, with partial recovery at reperfusion (P<0.005). Hearts with impaired function in the recipient showed marked variations in HEP levels at reperfusion, and those organs with RV dysfunction failed to replenish their energy stores. However, these organs were not different from normally functioning allografts in terms of endothelial activation and clinical risk factors. There was poor correlation between pressure-volume and HEP data in either donor or recipient studies. Hearts followed-up with HEP and pressure-volume studies showed improvement in the recipient, despite functioning against a higher pulmonary vascular resistance. CONCLUSIONS HEP are preserved over a wide range of contractile performance in the donor heart, with no metabolic difference between the two ventricles. No correlation with endothelial activation was seen either. Preservation efforts should be directed to the vulnerable periods of implantation and reperfusion.