Proinflammatory cytokines are infamous for their catabolic effects on tissues and joints in both inflammatory diseases and following the implantation of biomedical devices. However, recent studies indicate that many of these same molecules are critical for triggering tissue regeneration following injury. This review will discuss the role of inflammatory signals in regulating bone regeneration and the impact of both immunomodulatory and antiinflammatory pharmacologic agents on fracture healing, to demonstrate the importance of incorporating rational control of inflammation into the design of tissue engineering strategies.

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Modulation of the inflammatory response for enhanced bone tissue regeneration.

Excerpt Essentially all the hydroxyproline in the tissues of vertebrates is found in collagen, and, except for the small amount of hydroxyproline in elastin, no other animal protein contains signif...

Relationship of Hydroxyproline Excretion in Urine to Collagen Metabolism

Inflammation is an immediate response that plays a critical role in healing after fracture or injury to bone. However, in certain clinical contexts, such as in inflammatory diseases or in response to the implantation of a biomedical device, the inflammatory response may become chronic and result in destructive catabolic effects on the bone tissue. Since our previous review 3 years ago, which identified inflammatory signals critical for bone regeneration and described the inhibitory effects of anti-inflammatory agents on bone healing, a multitude of studies have been published exploring various aspects of this emerging field. In this review, we distinguish between regenerative and damaging inflammatory processes in bone, update our discussion of the effects of anti-inflammatory agents on bone healing, summarize recent in vitro and in vivo studies demonstrating how inflammation can be modulated to stimulate bone regeneration, and identify key future directions in the field.

Harnessing and modulating inflammation in strategies for bone regeneration.

Pediatric thyroid cancer is a rare disease with an excellent prognosis. Compared with adults, epithelial-derived differentiated thyroid cancer (DTC), which includes papillary and follicular thyroid cancer, presents at more advanced stages in children and is associated with higher rates of recurrence.

Because of its uncommon occurrence, randomized trials have not been applied to test best-care options in children. Even in adults that have a 10-fold or higher incidence of thyroid cancer than children, few prospective trials have been executed to compare treatment approaches. We recognize that treatment recommendations have changed over the past few decades and will continue to do so.

Respecting the aggressiveness of pediatric thyroid cancer, high recurrence rates, and the problems associated with decades of long-term follow-up, a premium should be placed on treatments that minimize risk of recurrence and the adverse effects of treatments and facilitate follow-up. We recommend that total thyroidectomy and central compartment lymph node dissection is the surgical procedure of choice for children with DTC if it can be performed by a high-volume thyroid surgeon. We recommend radioactive iodine therapy for remnant ablation or residual disease for most children with DTC. We recommend long-term follow-up because disease can recur decades after initial diagnosis and therapy.

Considering the complexity of DTC management and the potential complications associated with therapy, it is essential that pediatric DTC be managed by physicians with expertise in this area.

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The Treatment of Differentiated Thyroid Cancer in Children: Emphasis on Surgical Approach and Radioactive Iodine Therapy

Hair growth from the vertex, temple, mustache, finger, arm and leg of three Japanese men (60, 30, and 21 years of age) was measured by direct observation from October, 1966 to November 1968. Detailed information regarding hair growth cycles in the regions tested is presented.

Human hair cycle

Atavistic residues of aggressive behavior prevailing in animal life, determined by testosterone, remain attenuated in man and suppressed through familial and social inhibitions. However, it still manifests itself in various intensities and forms from; thoughts, anger, verbal aggressiveness, competition, dominance behavior, to physical violence. Testosterone plays a significant role in the arousal of these behavioral manifestations in the brain centers involved in aggression and on the development of the muscular system that enables their realization. There is evidence that testosterone levels are higher in individuals with aggressive behavior, such as prisoners who have committed violent crimes. Several field studies have also shown that testosterone levels increase during the aggressive phases of sports games. In more sensitive laboratory paradigms, it has been observed that participant’s testosterone rises in the winners of; competitions, dominance trials or in confrontations with factitious opponents. Aggressive behavior arises in the brain through interplay between subcortical structures in the amygdala and the hypothalamus in which emotions are born and the prefrontal cognitive centers where emotions are perceived and controlled. The action of testosterone on the brain begins in the embryonic stage. Earlier in development at the DNA level, the number of CAG repeats in the androgen receptor gene seems to play a role in the expression of aggressive behavior. Neuroimaging techniques in adult males have shown that testosterone activates the amygdala enhancing its emotional activity and its resistance to prefrontal restraining control. This effect is opposed by the action of cortisol which facilitates prefrontal area cognitive control on impulsive tendencies aroused in the subcortical structures. The degree of impulsivity is regulated by serotonin inhibiting receptors, and with the intervention of this neurotransmitter the major agents of the neuroendocrine influence on the brain process of aggression forms a triad. Testosterone activates the subcortical areas of the brain to produce aggression, while cortisol and serotonin act antagonistically with testosterone to reduce its effects.

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Testosterone and Aggressive Behavior in Man

Clusters of poorly demarcated neurons, called nuclei, situated in the hypothalamic area are the source of hormones which through the succession of their actions on the pituitary and the peripheral endocrine glands, regulate and control major functions of the organism, namely, reproduction, energy, metabolism and adaptation. The significance of these vital functions is obvious; thus our understanding of the course of endocrine hypothalamus functioning throughout the length of life is evidently of paramount importance. Numerous genetic and intrinsic or environmental factors can influence or derange the endocrine function of the hypothalamus. However, the most consistent and inevitable factor, one which we now know commences earlier than was once assumed, is aging.

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The aging of the endocrine hypothalamus and its dependent endocrine glands.

The endocrinology of baldness Male pattern baldness, scientifically known as androgenetic alopecia (AGA), is a very common condition, universally prevalent, which progresses with aging. The loss of scalp hair of any degree both in men and women is a cause of considerable psychological distress associated with a loss of self-esteem and feelings of diminished self-image, resulting in introversion and depression. Particularly among men, the very manifest obviousness of baldness is often a source of major psychological anguish. Two clinical features of male baldness have been recognized: a predisposition to scalp hair loss inherited from the father or grandfather(s) and a negative connection of scalp hair loss with the testes. Eunuchs and pre-pubertally castrated men who fail to develop body hair have normal scalp hair which shows no sign of loss with age. However, castrates receiving lifelong replacement therapy with testosterone show scalp hair loss and various degrees of baldness. The complete restoration of body hair in eunuchs and castrates by the administration of testosterone established the notion that androgens are responsible for hair growth, but at the same time it revealed the hair loss effect of testosterone on scalp hair. 1 The paradox of a diametrically different action of a hormone on its receptors aroused much interest and initiated research into the dual effect of testosterone and into the investigation of this biological aberrance that has created an unwanted phenotypic manifestation which, because of its great prevalence, the psychological impact and the difficulties and cost of treatment, is an important medicosocial problem. This review is a discussion on the endocrine connections at the hormonal, molecular and genetic levels with male and female scalp hair loss and on the psychological effects. Also discussed is the theory that baldness may be an early prognostic marker of prostate cancer and cardiovascular disease. The psychological effecTs of baldness Head hair is an essential complimentary feature to the face in the composition of an individual’s physiognomy and, by virtue of its natural qualities and its capacity to be modeled artistically, contributes significantly to an individual’s self-perceived image as well as to the response of others. It is therefore only natural that hair loss to any degree will have a negative psychological impact on the quality of a person’s life. Several studies have documented the psychological distress caused by baldness and investigated its parameters.

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The endocrinology of baldness.

Over the past two decades a plethora of publications and clinical practice data have established that subclinical thyroid dysfunction is a common condition occurring much more frequently than the overt expression of thyroid disease. Subclinical hypothyroidism is considered to be the most common of these entities. However, far more common and relatively less studied is exogenous sublinical hyperthyroidism (SubHyper) caused by L-thyroxine (T4) administration to thyroidectomized or hypothyroid patients or patients with simple or nodular goiter. Despite iodination, simple goiter is still prevalent and single or multiple nodules are now detected by ultrasound screening in 25-30% of adults, who are accordingly frequently given long-term T4 treatment. Approximately half of European Endocrinologists administer T4 permanently to patients with the above entities with the aim of suppressing TSH levels. Furthermore, in the USA the Colorado Study demonstrated that 40% of patients receiving thyroid hormones had abnormal [corrected] TSH levels (i.e. lower than 0.3 or higher than 5.1 mU/L); of these, 0.9% had hyperthyroidism and 20.7% subclinical hyperthyroidism [corrected] These facts render exogenous SubHyper an everyday problem for the endocrinologist. Exogenous SubHyper differs in many aspects from endogenous, its principal difference being that it is an iatrogenic thyroid disorder induced by the endocrinologist. The management of exogenous SubHyper relies on appropriate adjustment of T4 dosage taking into consideration a) individual requirements in T4, sex, age and the presence of cardiovascular disease or other co-morbidity, b) the recognition that small changes in serum FT4 have a logarithmic effect on TSH, c) the variability of FT4-TSH interactions between individuals, d) the instability of T4 preparations and its bioavailability, and e) the values of serum FT4 and FT3 that accompany a suppressed TSH. This last parameter is of importance since it is the free thyroid hormones values in the serum that generate and reflect the thyroid metabolic state of the organism rather than the degree of TSH suppression.

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The problem of exogenous subclinical hyperthyroidism.

The effect of cortisone and an anabolic steroid on plasma hydroxyproline (HOP) was investigated in young male rabbits, following operative fracture of the radius. The action of these hormones was studied in three groups of animals, a cortisone (hydrocortisone sodium succinate 5mg/kg every day), an anabolic (norandronolone-19-phenylpropionate 5 mg/kg every other day) and a cortisone plus anabolic treated group. A fourth group of animals served as controls. Plasma HOP was found to increase during the fracture healing in control animals, particularly in the first week and during callus remodelling. Cortisone produced elevation of HOP level during the first two weeks followed by a decrease to low normal values. Animals treated with the anabolic did not present the initial rise but a sustained increase during callus remodelling. When both the anabolic and cortisone were administered, a curve similar to that of cortisone-treated animals was obtained. The initial increase of HOP is attributed to bone destruction and to a lesser degree to synchronous bone formation at the site of the fracture. This catabolic process seems to be enhanced by cortisone and inhibited by the anabolic. When, however, the two hormones are given together the protective anticatabolic effect of the anabolic is almost abolished.

https://www.tandfonline.com/doi/pdf/10.3109/17453677508989188

Menelaos L. Batrinos

Papers

Testosterone and Aggressive Behavior in Man

The aging of the endocrine hypothalamus and its dependent endocrine glands.

The endocrinology of baldness.

The problem of exogenous subclinical hyperthyroidism.

Effect of cortisone and an anabolic steroid upon plasma hydroxyproline during fracture healing in rabbits.