Clinical outcomes of absorbable plates (hydroxyapatite-poly-l-lactide composites) for phalangeal fractures - case reports.

We report two cases of the basal phalanx fractures of the thumb treated with absorbable mesh plates. In both cases, the mesh plates specifically tailored for each fracture were effective in obtaining bone union and healing. We conclude that absorbable mesh plates could be a practical option for phalangeal fractures, especially where proprietary pre-molded metallic plates do not neatly fit the reduced fracture area.

Evaluation of apocynin in vitro on high glucose-induced oxidative stress on tenocytes.

AIMS: The purpose of this study was to evaluate the in vitro effects of apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase (NOX) and a downregulator of intracellular reactive oxygen species (ROS), on high glucose-induced oxidative stress on tenocytes. METHODS: Tenocytes from normal Sprague-Dawley rats were cultured in both control and high-glucose conditions. Apocynin was added at cell seeding, dividing the tenocytes into four groups: the control group; regular glucose with apocynin (RG apo+); high glucose with apocynin (HG apo+); and high glucose without apocynin (HG apo-). Reactive oxygen species production, cell proliferation, apoptosis and messenger RNA (mRNA) expression of NOX1 and 4, and interleukin-6 (IL-6) were determined in vitro. RESULTS: Expression of NOX1, NOX4, and IL-6 mRNA in the HG groups was significantly higher compared with that in the RG groups, and NOX1, NOX4, and IL-6 mRNA expression in the HG apo+ group was significantly lower compared with that in the HG apo- group. Cell proliferation in the RG apo+ group was significantly higher than in the control group and was also significantly higher in the HG apo+ group than in the HG apo- group. Both the ROS accumulation and the amounts of apoptotic cells in the HG groups were greater than those in the RG groups and were significantly less in the HG apo+ group than in the HG apo- group. CONCLUSION: Apocynin reduced ROS production and cell death via NOX inhibition in high-glucose conditions. Apocynin is therefore a potential prodrug in the treatment of diabetic tendinopathy.Cite this article: Bone Joint Res 2020;9(1):23-28.

OPTIMAL INJECTION DEPTH FOR COLLAGENASE CLOSTRIDIUM HISTOLYTICUM DETERMINED BY ULTRASONOGRAPHY IN THE TREATMENT OF DUPUYTREN´S DISEASE.

INTRODUCTION: A non-surgical procedure for the treatment of Dupuytrens disease is a palmar injection of Collagenase Clostridium Histolyticum to the recommended depth of “around 2-3 mm”. However, there is little supporting evidence from the literature to substantiate this. The aim of this study was to evaluate the “optimal depth” for injection of Collagenase Clostridium Histolyticum by ultrasonography for the treatment of Dupuytrens disease. MATERIAL AND METHODS: A total of 43 patients were enrolled in this study. We marked the collagenase injection point on the skin above the cord before injection. We then measured the distance from the surface of the skin to the middle of the cord by ultrasonography long axis imaging and defined this as the “optimal depth”. RESULTS: The average depth from the skin to the centre of the cord was 2.4 mm. The average distance from the surface of the skin to the proximal surface of the cord was 1.0 mm and the average thickness of the cord was 2.7 mm. CONCLUSION: By precise measurement of individual cases utilising ultrasonography we were able to confirm that the recommendations for injection depth as provided by the supplier of Collagenase Clostridium Histolyticum (2-3 mm) were in agreement with our findings. However no objective guide was supplied as with regards to interindividual variability between patients and we suggest that the use of preliminary ultrasonography will likely provide improved outcomes.

The effects of high glucose condition on rat tenocytes in vitro and rat Achilles tendon in vivo.

OBJECTIVES: The aim of this study was to investigate the effect of hyperglycaemia on oxidative stress markers and inflammatory and matrix gene expression within tendons of normal and diabetic rats and to give insights into the processes involved in tendinopathy. METHODS: Using tenocytes from normal Sprague-Dawley rats, cultured both in control and high glucose conditions, reactive oxygen species (ROS) production, cell proliferation, messenger RNA (mRNA) expression of NADPH oxidase (NOX) 1 and 4, interleukin-6 (IL-6), matrix metalloproteinase (MMP)-2, tissue inhibitors of matrix metalloproteinase (TIMP)-1 and -2 and type I and III collagens were determined after 48 and 72 hours in vitro. In an in vivo study, using diabetic rats and controls, NOX1 and 4 expressions in Achilles tendon were also determined. RESULTS: In tenocyte cultures grown under high glucose conditions, gene expressions of NOX1, MMP-2, TIMP-1 and -2 after 48 and 72 hours, NOX4 after 48 hours and IL-6, type III collagen and TIMP-2 after 72 hours were significantly higher than those in control cultures grown under control glucose conditions. Type I collagen expression was significantly lower after 72 hours. ROS accumulation was significantly higher after 48 hours, and cell proliferation after 48 and 72 hours was significantly lower in high glucose than in control glucose conditions. In the diabetic rat model, NOX1 expression within the Achilles tendon was also significantly increased. CONCLUSION: This study suggests that high glucose conditions upregulate the expression of mRNA for NOX1 and IL-6 and the production of ROS. Moreover, high glucose conditions induce an abnormal tendon matrix expression pattern of type I collagen and a decrease in the proliferation of rat tenocytes.Cite this article: Y. Ueda, A. Inui, Y. Mifune, R. Sakata, T. Muto, Y. Harada, F. Takase, T. Kataoka, T. Kokubu, R. Kuroda. The effects of high glucose condition on rat tenocytes in vitro and rat Achilles tendon in vivo. Bone Joint Res 2018;7:362-372. DOI: 10.1302/2046-3758.75.BJR-2017-0126.R2.

Effects of platelet-rich plasma and triamcinolone acetonide on interleukin-1ß-stimulated human rotator cuff-derived cells.

OBJECTIVES: Triamcinolone acetonide (TA) is widely used for the treatment of rotator cuff injury because of its anti-inflammatory properties. However, TA can also produce deleterious effects such as tendon degeneration or rupture. These harmful effects could be prevented by the addition of platelet-rich plasma (PRP), however, the anti-inflammatory and anti-degenerative effects of the combined use of TA and PRP have not yet been made clear. The objective of this study was to determine how the combination of TA and PRP might influence the inflammation and degeneration of the rotator cuff by examining rotator cuff-derived cells induced by interleukin (IL)-1ß. METHODS: Rotator cuff-derived cells were seeded under inflammatory stimulation conditions (with serum-free medium with 1 ng/ml IL-1ß for three hours), and then cultured in different media: serum-free (control group), serum-free + TA (0.1mg/ml) (TA group), serum-free + 10% PRP (PRP group), and serum-free + TA (0.1mg/ml) + 10% PRP (TA+PRP group). Cell morphology, cell viability, and expression of inflammatory and degenerative mediators were assessed. RESULTS: Exposure to TA significantly decreased cell viability and changed the cell morphology; these effects were prevented by the simultaneous administration of PRP. Compared with the control group, expression levels of inflammatory genes and reactive oxygen species production were reduced in the TA, PRP, and TA+PRP groups. PRP significantly decreased the expression levels of degenerative marker genes. CONCLUSIONS: The combination of TA plus PRP exerts anti-inflammatory and anti-degenerative effects on rotator cuff-derived cells stimulated by IL-1ß. This combination has the potential to relieve the symptoms of rotator cuff injury.Cite this article: T. Muto, T. Kokubu, Y. Mifune, A. Inui, R. Sakata, Y. Harada, F. Takase, M. Kurosaka. Effects of platelet-rich plasma and triamcinolone acetonide on interleukin-1ß-stimulated human rotator cuff-derived cells. Bone Joint Res 2016;5:602-609. DOI: 10.1302/2046-3758.512.2000582.

Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

Ghrelin.

BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

Chronic overproduction of ghrelin in the hypothalamus leads to temporal increase in food intake and body weight.

Ghrelin is known to be a critical stimulator of feeding behavior mainly via actions in the hypothalamus. However, its functional contribution to the control of energy homeostasis under chronic elevated conditions is unknown. Here we show that overproduction of ghrelin via an AAV viral delivery system in the hypothalamus leads to an increase in food intake associated with increases in body weight. However, this increase in food intake is only temporary and is diminished and no longer significant after 3 weeks. Analysis of brain sections of mice 6 weeks after AAV-ghrelin virus injection demonstrates unaltered neuropeptide Y levels but strongly up-regulated pro-opiomelanocortin levels indicating that a compensatory mechanism has been activated to counter regulate the feeding stimulatory actions of ghrelin. This demonstrates that control mechanism exists that is activated under conditions of prolonged high ghrelin levels, which could potentially be utilized to control feeding and the development of obesity.

Dose- and time-dependent effects of triamcinolone acetonide on human rotator cuff-derived cells.

OBJECTIVES: To investigate the appropriate dose and interval for the administration of triamcinolone acetonide (TA) in treating tendinopathy to avoid adverse effects such as tendon degeneration and rupture. METHODS: Human rotator cuff-derived cells were cultured using three media: regular medium (control), regular medium with 0.1 mg/mL of TA (low TA group), and with 1.0 mg/mL of TA (high TA group). The cell morphology, apoptosis, and viability were assessed at designated time points. RESULTS: In the low TA group, the cells became flattened and polygonal at seven days then returned to normal at 21 days. The cell apoptosis ratio and messenger ribonucleic acid expression of caspase-3, 7, 8, and 9 increased, and viability was reduced in the low and high groups at seven days. In the low TA group, apoptosis and viability returned to normal at 21 days, however, in the high TA group, the cell morphology, apoptosis ratio, caspase-3, 7, 8, and 9 and viability did not return by day 21. Re-administration was performed in the low TA group at 7-, 14-, and 21-day intervals, and cell viability did not return to the control level at the 7- and 14-day intervals. CONCLUSION: A 0.1 mg/mL dose of TA temporarily decreased cell viability and increased cell apoptosis, which was recovered at 21 days, however, 1 mg/mL of TA caused irreversible damage to cell morphology and viability. An interval > three weeks was needed to safely re-administer TA. These findings may help determine the appropriate dose and interval for TA injection therapy. Cite this article: Bone Joint Res 2014;3:328-34.

Insulin secretion and interleukin-1ß dependent mechanisms in human diabetes remission after metabolic surgery.

To compare endocrine, metabolic, and inflammatory changes induced by gastric bypass (GB) and sleeve gastrectomy (SG) in patients with type 2 diabetes mellitus (T2DM), and to investigate the mechanisms of success after metabolic surgery. Sixteen GB and 16 SG patients were followed up before and at 1 year after surgery. The 75-g oral glucose tolerance test (OGTT) was performed before and after surgery. Glucose homeostasis, serum interleukin-1ß, plasma gut hormones and adipokines, and the United Kingdom Prospective Diabetes Study (UKPDS) ten-year cardiovascular risks were evaluated. The diabetes remission rate was significantly higher in GB than SG. Changes in the area under the curve (AUC) for glucose were greater in those with complete and partial remission after GB and remitters after SG than non-remitters after SG, whereas changes in AUC for C-peptide were higher in complete and partial remitters after GB than non-remitters after SG. Insulinogenic index was enhanced and serum interleukin-1ß was reduced in complete remitters after GB and remitters after SG. Logistic regression analysis confirmed that insulinogenic index and interleukin-1ß, not insulin resistance, were the factors determining the success of diabetes remission after metabolic surgeries. GB and SG significantly reduced the ten-year risk of coronary heart disease and fatal coronary heart disease in T2DM patients after surgery, while GB had the additional benefit of reduced stroke risk. Human diabetes remission after metabolic surgery is through insulin secretion and interleukin-1ß dependent mechanisms. GB is superior to SG in cardiocerebral risk reduction in Asian non-morbidly obese, not well-controlled T2DM patients.

Increase in energy intake leads to a decrease in obestatin in restricting-type of anorexia nervosa.

Restricting-type of anorexia nervosa (AN-R) is a serious disorder affecting adolescents and young adults, and decreases quality of life over long period. Successful weight restoration is an important prognostic factor for disease outcome; however, the underlying mechanism of refeeding-resistance, a core psychopathology relevant to 'ambivalent' eating behaviors, remains unclear in this disorder. Obestatin plays an important role in the regulation of growth hormone release, appetite, and energy metabolism. However, the progress of these patients and changes in the levels of obestatin during treatment were not reported. The purpose of this study was to determine the changes in obestatin levels when energy intake increases in AN-R patients. As a result, obestatin was higher in AN-R patients than in control subjects as well as acyl ghrelin and des-acyl ghrelin. An increase in the intake calorie has decreased obestatin as well as des-acyl ghrelin. These findings indicate that the obestatin is an important factor in the diagnosis and treatment of AN-R, similarly to acyl ghrelin and des-acyl ghrelin. In the future, the research on the clinical application of the ghrelin peptide family and the receptor will be expected to progress.

Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival.

Cancer anorexia-cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut-brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia-cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia-cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia-cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia-cachexia.

Effects of exercise on the levels of peptide YY and ghrelin.

Ghrelin and peptide YY (PYY) are brain-gut peptides that have a variety of physiological functions and are involved in energy regulation. Thus far, abnormalities in the expression and secretion of ghrelin and PYY are known to occur in lifestyle-related diseases, including obesity, and the improvement of these abnormalities has become an important challenge. Exercise has recently been reported to influence ghrelin and PYY concentrations. Exercise increases the PYY secretion. The effects of exercise on ghrelin levels vary with the study subject, timing of exercise, and duration of exercise. Here, we review the findings of recent studies on the association of PYY and ghrelin with obesity, particularly, on the influence of exercise on PYY and ghrelin levels.

Changes in acyl ghrelin, des-acyl ghrelin, and ratio of acyl ghrelin to total ghrelin with short-term refeeding in female inpatients with restricting-type anorexia nervosa.

Restricting type of anorexia nervosa (AN-R) is a serious disorder affecting adolescents and young adults and decreases quality of life over a long period. Successful weight restoration is an important prognostic factor for disease outcome; however, the underlying mechanism of refeeding resistance, a core psychopathology relevant to 'ambivalent' eating behaviors, remains unclear in this disorder. Ghrelin plays an important role in the regulation of growth hormone release, appetite, and energy metabolism. However, the early progress of these patients and changes in the levels of acyl ghrelin and des-acyl ghrelin during treatment were not reported. The purpose of this study was to determine the changes in ghrelin levels (acyl and des-acyl) during early treatment. As a result, des-acyl ghrelin in AN-R patients is higher than in control subjects before the therapy, but it decreases with treatment. The plasma des-acyl ghrelin level in AN-R patients started decreasing more rapidly and in early stage of the hospitalization than ever reported, and after 8 weeks, it is significantly lower than in control subjects. It means that des-acyl ghrelin is sensitive and changeable with their nutrition state. Furthermore, the ratio of the acyl ghrelin to total ghrelin increases with 8 weeks treatment. Eight weeks after, energy intake of the AN-R patients is recovered near the normal range with a daily energy intake of 1 700+/-93.54 kcal. These findings may be valuable for future AN-R treatments in order to increase acyl ghrelin and decrease des-acyl ghrelin, thereby influencing the refeeding outcome.

Centrally administered neuromedin S inhibits feeding behavior and gastroduodenal motility in mice.

Neuromedin S (NMS) was recently identified as an endogenous ligand for the FM-4/TGR-1 receptor in the rat hypothalamus. No previous studies have examined the effect of NMS on gut motility. We examined the effects of intracerebroventricular administration of NMS on food intake in food-deprived and free-feeding mice, and on gastroduodenal motility by using a manometric method, and gastric emptying in mice. We found that NMS decreased food intake and the gastric emptying rate. It also disrupted the motor activity in the antrum and duodenum of conscious food-deprived mice. These results suggest that NMS influences gut motility as well as feeding behavior.

Reduced carbohydrate intake in citrin-deficient subjects.

Citrin is the liver-type aspartate-glutamate carrier that resides within the inner mitochondrial membrane. Citrin deficiency (due to homozygous or compound heterozygous mutations in the gene SLC25A13) causes both adult-onset type II citrullinaemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). Clinically, CTLN2 is characterized by hyperammonaemia and citrullinaemia, whereas NICCD has a much more varied and transient presentation that can include multiple aminoacidaemias, hypoproteinaemia, galactosaemia, hypoglycaemia, and jaundice. Personal histories from CTLN2 patients have repeatedly described an aversion to carbohydrate-rich foods, and clinical observations of dietary and therapeutic outcomes have suggested that their unusual food preferences may be directly related to their pathophysiology. In the present study, we monitored the food intake of 18 Japanese citrin-deficient subjects whose ages ranged from 1 to 33 years, comparing them against published values for the general Japanese population. Our survey confirmed a marked decrease in carbohydrate intake, which accounts for a smaller proportion of carbohydrates contributing to the total energy intake (PFC ratio) as well as a shift towards a lower centile distribution for carbohydrate intake relative to age- and sex-matched controls. These results strongly support an avoidance of carbohydrate-rich foods by citrin-deficient patients that may lead to worsening of symptoms.

NPY Y2 and Y4 receptors selective ligands: promising anti-obesity drugs?

Neuropeptide Y (NPY), a potent orexigen peptide widely produced and distributed in arcuate neurons in the hypothalamus, is a promising candidate for the control of appetitive ingestive behavior. In mammals, the signaling is mediated via at least five different cell surface receptors, denoted as Y(1), Y(2), Y(4), Y(5) and Y(6). Obesity is an important public health problem in the world, particularly in developed societies, and has taken on pandemic proportions. The therapeutics of obesity, including appetite suppressants, has increased 453% over the past decade, although issues concerning safety, efficacy, and little knowledge of the pharmacological activity result in the still modest effects of the anti-obesity drugs presently used. Ligands for Y receptors may be of benefit for the treatment of obesity, and recent findings have indicated a promising role of Y(2) and Y(4) in protecting against diet-induced obesity. This review highlights the supporting evidence therapeutic potential of Y(2) and Y(4) receptors antagonists as additional intervention to treat human obesity.

Neuropeptide y receptor selective ligands in the treatment of obesity.

Obesity is a serious public health problem throughout the world, affecting both developed societies and developing countries. The central nervous system has developed a meticulously interconnected circuitry in order to keep us fed and in an adequate nutritional state. One of these consequences is that an energy-dense environment favors the development of obesity. Neuropeptide Y (NPY) is one of the most abundant and widely distributed peptides in the central nervous system of both rodents and humans and has been implicated in a variety of physiological actions. Within the hypothalamus, NPY plays an essential role in the control of food intake and body weight. Centrally administered NPY causes robust increases in food intake and body weight and, with chronic administration, can eventually produce obesity. NPY activates a population of at least six G protein-coupled Y receptors. NPY analogs exhibit varying degrees of affinity and specificity for these Y receptors. There has been renewed speculation that ligands for Y receptors may be of benefit for the treatment of obesity. This review highlights the therapeutic potential of Y(1), Y(2), Y(4), and Y(5) receptor agonists and antagonists as additional intervention to treat human obesity.