Wound healing in man: tensile strength of healing wounds in some patient groups.

The healing of test wounds was studied in 108 patients, in whom some impairment of wound healing was suspected. A 5 cm skin wound was performed in the forearm and the strength of the wound was tested after 5 days using the technique described by Sandblom and associates with two measurements in each wound. No differences in wound strength could be registered between the two wounds in each patient, between males and females nor in patients with malignant disease compared to other patients. Patients with low serum protein or serum albumin values had significantly weaker wounds than patients with normal protein values. Patients over 80 years of age had wounds somewhat weaker than those below 70, the difference having a statistical significance of 6%. The wound strength in patients was compared to values found elsewhere for wounds in rabbits, rats, and piglets. The pigs had much higher values than others, rabbits slightly stronger than and rats about equal to humans.     

Growth hormone normalizes vertebral strength in ovariectomized rats

Ten-month-old lactating breeders were ovariectomized and kept on a low calcium diet. One month after ovariectomy, the rats were dosed once daily for 6 months with either a low dose of growth hormone (GH) (0.05 mg), a high dose of GH (1 mg), estrogen plus gestagen (E-G) [17-estradiol (0.1 mg); norethisterone-acetate (0.05 mg)], or a combination of GH and E-G. Mechanical competence, apparent dry density, apparent ash density and ash concentration were measured in the fourth lumbar vertebral body. The reduced mechanical strength, ash density and ash concentration found in the vertebral body of ovariectomized animals were prevented by the high dose of GH alone, or in combination with E-G. E-G alone partly prevented the decline in ash density and ash concentration, but did not affect the reduced mechanical strength seen after ovariectomy. Only minor effects were observed after treatment with the low dose of GH, alone or in combination with E-G. In conclusion this study shows that GH administration prevents the decline in mechanical strength and bone mineral density seen in rats after ovariectomy.     

Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats

The effects of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats were examined to evaluate its potential use as a therapeutic agent for osteoporotic fractures. Three months postovariectomy, bilateral tibial shaft fractures were induced and stabilized by intramedullary nailing with Kirschner wires. Saline, 17beta-estradiol (Sigma Chemical Corp, St Louis, Mo), or recombinant human parathyroid hormone (1-84) (Korean Green-Cross Pharm Corp, Seoul, Korea) was given once a day for 30 consecutive days during fracture healing. Fracture healing was assessed by morphometric and mechanical analysis of fracture callus. Intermittent parathyroid hormone administration increased the morphometric and mechanical parameters in a dose-dependent manner. A bone-resorption inhibiting agent, 17beta-estradiol did not offer advantage in terms of fracture healing in ovariectomized rats. Findings suggest intermittent parathyroid hormone administration may benefit osteoporosis and fracture.     

Postmenopausal hormone replacement therapy: effects on normal mammary gland in humans and in a mouse postmenopausal model

Endogenous estrogen exposure has long been implicated in the causation of breast cancer through a mechanism of epithelial cell proliferation. Whether estrogen, progesterone, or both exhibit mitogenic activity and promote carcinogenesis in the human breast has been the subject of considerable debate. The purpose of this review article is to examine the evidence for the effects of hormone replacement therapy in its various forms on the biology of the postmenopausal breast both in humans and in an animal model, and to identify the gaps in knowledge that research will need to address to further understand this complex issue.     

Hormone replacement therapy and breast cancer risk in California

Numerous studies have documented increased breast cancer risks with hormone replacement therapy (HRT), but these do not give a woman her specific absolute risk for the remainder of her life. This article estimates the magnitude of the effect of HRT on breast cancer incidence in California and calculates a woman's cumulative risk of breast cancer with different formulations and durations of HRT use. The effects of HRT on the underlying breast cancer incidence were estimated using the attributable fraction method, applying HRT prevalence data from the 2001 California Health Interview Survey and published rates of higher relative risk (RR) from HRT use from the Women's Health Initiative (WHI) study and Million Women's Survey (MWS). The annual number of breast cancers potentially attributable to HRT in California was estimated, along with individual cumulative risk of breast cancer for various ages to 79 years according to HRT use, duration, and formulation. Using the WHI data, 829 of 19,000 breast cancers (4.3%) in California may be attributable to HRT. This figure increases to 3401 (17.4%) when the MWS RRs are applied. Use of estrogen-only HRT or short-term (approximately 5 years) use of combined HRT has a minimal effect on the cumulative risk calculated to the age of 79 years; application of the MWS data to a Californian woman commencing HRT at the age of 50 years (no HRT, 8.5%; estrogen only, 8.6%; combined, 9.1%). Prolonged (approximately 10 years) use of combined HRT increases the cumulative risk to 10.3%. This article demonstrates that HRT will generate a small additional risk of breast cancer in an individual. The reduction in perimenopausal symptoms may be considered sufficient to warrant this extra risk. However, this view needs to be balanced because the small increases in individual risk will be magnified, producing a noticeable change in population cancer caseload where HRT use is high.     

Early period of fracture healing in ovariectomized rats

Objective. To evaluate the effect of osteoporosis on fracture healing through observing the hlstomorphological changes, bone mineral density of callus and expression and distribution of transforming growth factor beta 1 (TGF-β1 ), basic fibroblast growth factor (bFGF)and bone morphogenetic protein.2 (BMP-2) in ovariectomized rats. Methods. Sixty female Sprague-Dawley rats ( aged 12 weeks and weighing 235 g on average ) were randomly divided into an ovariectomized (OVX) group (n =30) anda sham-operated (SO) group ( n = 30). Ovariectomy was performed in the OVX rats and same incision was made in the SO rats. Three months later, fracture of femoral shaft was made on all the rats. Then they were killed at different time points. Callus formation was observed with histological and imethods. Results: A reduction in callus and bone mineral density in the healing femur and a decrease of osteoblasts expressing TGF-β1 near the bone trabecula were observed in the OVX rats 3-4 weeks after fracture.Histomorphological analysis revealed a higher content of soft callus in the OVX rats than that in the SO rats.Immunohistochemistry results showed that no remarkable difference in expression and distribution of BMP-2 and bFGF between the OVX and SO groups was found. Conclusions: Osteoporosis influences the quantity and quality of callus during the early period of fracture healing. The effect of osteoporosis on fracture healing has no relationship with the expression of BMP-2 or bFGF. The decreased expression of TGF-I31 in osteoblasts may cause a decrease in quality of facture healing after osteoporosis.     

Effects of plasma fibronectin on the healing of full-thickness skin wounds in streptozotocin-induced diabetic rats

BACKGROUND: Fibronectin has been shown to assist in wound healing. Impaired wound healing in diabetes mellitus is characterized by a reduction in plasma fibronectin (pFn) at the wound site. This study investigated whether topical application of pFn could improve the impaired wound healing in diabetic rats. MATERIALS AND METHODS: Full-thickness skin wounds were created on the backs of streptozotocin (STZ)-induced diabetic rats. Immediately, human pFn was introduced into the wound bed, while wounds receiving human serum albumin or normal saline were used as controls. Wound closure was monitored using well-recognized wound-healing parameters: epithelialization, vascularization, collagen deposition, and migration of fibroblasts were examined histologically. Transforming growth factor (TGF)-beta1 was measured by immunochemistry. Hydroxyproline levels also were assessed in the wound skin. RESULTS: Wound closure was significantly accelerated by local application of pFn. Furthermore, pFn-treated wounds showed increased fibroblast vascularization, collagen regeneration, and epithelialization. The numbers of infiltrating fibroblasts expressing TGF-beta1 and hydroxyproline levels in pFn-treated wounds were significantly higher than those in the controls. CONCLUSIONS: pFn can improve the impaired healing of diabetic wounds and this effect might involve an increase in the activity of fibroblasts and increased release of TGF-beta1.     

Effects of estrogen and progestin replacement on the urogenital tract of the ovariectomized cynomolgus monkey

Menopause is presumed to have a causative role in the development of female urinary incontinence. While some clinical trials have shown that estrogen can affect urinary tract function, our knowledge of the pathophysiologic changes resulting from menopause and hormone replacement therapy is poor. The cynomolgus monkey is a well-established model for study of menopause and hormone replacement therapy, particularly in the cardiovascular arena. We have utilized this animal model to determine the histologic effects of estrogen and estrogen/progestin replacement therapy in the proximal urethra and vagina. Estrogen and estrogen/progestin replacement induced an increase in the amount of vaginal but not urethral epithelium. Hormone replacement also resulted in a significant increase in the loose, vascular component of the connective tissue layer of the urethra. The cynomolgus macaque shows promise as a useful model for further study of the effects of hormone replacement on the lower urinary tract. © 1996 Wiley-Liss, Inc.     

Experimental wound healing: increased breaking strength and collagen synthetic activity in abdominal fascial wounds healing with secondary closure of the skin

Delayed primary closure or secondary closure of skin and subcutaneous fat in contaminated laparotomy incisions virtually eliminates the risk of wound abscess in clinical practice. Incisional hernias rarely develop in these wounds. This experimental study offers a possible explanation. Longitudinal incisions in the linea alba of female Wistar rats healed under skin incisions which were either sutured ('closed' subgroup) or left to close by secondary intention ('open' subgroup). Postoperative breaking strengths and collagen contents (measured as hydroxyproline) were studied at intervals of 3-120 days. Measurable strength developed by 5 days, at which time 'open' subgroup wounds were found to be weaker and to have less collagen. At all other times, however, 'open' subgroup wounds were stronger, a property which could be ascribed at earlier, but not at later, periods (42 or 120 days), to a higher content and concentration of collagen. At 3 days the rate of collagen production was significantly (P less than 0.025) lower in 'open' than in 'closed' subgroup wounds but the converse was true at 6 and 9 days (P less than 0.025), thus accounting for the changes in biomechanical properties. It is suggested that initially the stimulus for collagen synthesis is greater in the 'open' wounds and this leads to the development of a collagenous structure which is better adapted to resist tensile forces.     

Effects of single and concurrent intermittent administration of human parathyroid hormone and bisphosphonate cimadronate on bone mineral densities of femur in ovariectomized rats

This study compared the single administration of human parathyroid hormone [hPTH(1-34)] or bisphosphonate cimadronate (YM-175), and concurrent therapy with both of these agents for restoration of lost bone mineral density (BMD) in ovariectomized (OVX) rats. Animals were untreated for 4 weeks after surgery, and then injected s.c. with vehicle (OVX+V), hPTH(l-34) (30g/kg) (OVX+P), YM-175 (5g/kg) (OVX+Y), or a combination of these two (OVX+P+Y), 3 days a week, for 8 weeks, and killed. BMD of distal, middle, and total femur were determined by dual-energy X-ray absorptiometry (DXA). BMD of distal and total femur, but not of midfemur, decreased at both 4 weeks and 12 weeks after ovariectomy. In the distal femoral BMD, although OVX+Y failed to restore lost BMD in OVX rats, either OVX+P or OVX+P+Y could reverse BMD lost due to OVX. Midfemoral BMD was unchanged through OVX or both single treatments, whereas this parameter was increased only in OVX+P+Y. These results suggest that concurrent treatment with PTH and YM-175 results in a bone anabolic effect not only in cancellous bone but also in cortical bone.     

卵巢摘除大鼠外周血单核细胞ER-mRNA表达与骨小梁退变的相关研究

目的探讨外周血单核细胞及其雌激素受体（ＥＲ）ｍＲＮＡ表达水平，在绝经后骨质疏松发生机理中所超的作用。方法成年雌性ＳＤ大鼠３０只，随机分３组，去势组（ＯＶＸ组），假手术组（Ｓｈａｍ组），ＯＶＸ＋Ｐｒｅｍａｒｉｎ组（ＥＲＴ组）。术后６周后采各大鼠心脏血，分别以①用放免法测定血清雌二醇；②外周血单核细胞计数以及分离培养纯化单核细胞后运用ＲＴ－ＰＣＲ法检测ＥＲ－ｍＲＮＡ；③各组行骨组织形态计量学测定。结果     

Elevated Aromatase Expression in Osteoblasts Leads to Increased Bone Mass Without Systemic Adverse Effects

The stimulatory effects of testosterone (T) on bone can either be through a direct activation of the androgen receptor (AR) or mediated through aromatization of T to estradiol (E2), followed by activation of estrogen receptors (ERs) in bone. Aromatase expression in osteoblasts and reproductive tissues is dependent on different promoters, which are differentially regulated. To study the effect of elevated local aromatization of T to E2 in bone, we developed a transgenic mouse model (Coll‐1α1‐Arom) that overexpresses the human aromatase gene under the control of the osteoblast specific rat type I α I procollagen promoter. The Coll‐1α1‐Arom mice expressed human aromatase mRNA specifically in bone and had unaffected serum E2 and T levels. Male Coll‐1α1‐Arom mice had clearly increased total body BMD, trabecular BMD, cortical BMD, and cortical thickness associated with elevated osteoprotegerin mRNA levels and reduced number of osteoclasts (p < 0.01). Treatment of ovariectomized mice with T increased cortical and trabecular thickness in the Coll‐1α1‐Arom mice (p < 0.001) but not in the wildtype mice. In conclusion, elevated aromatase expression specifically in osteoblasts results in stimulatory estrogenic effects in bone without increasing serum E2 levels. Because osteoblast‐specific aromatase expression results in an increased ER to AR activation ratio in bone, we propose that activation of ERs results in a more pronounced increase in bone mass than what is seen after activation of the AR. Development of osteoblast‐specific inducers of aromatase expression might identify substances with stimulatory effects on bone without systemic adverse effects.     

辛伐他汀联合雌二醇对去卵巢大鼠骨质疏松的影响

目的探讨辛伐他汀联合雌二醇对大鼠骨质疏松的影响。方法 75只雌性SD大鼠随机分为5组:假手术组、去势组、辛伐他汀组、雌二醇组、联合药物组,15只/组,构建去卵巢大鼠骨质疏松模型,给予不同药物干预。检测骨代谢相关生化指标及骨生物力学指标,测定骨组织骨密度(bone mineral density,BMD)和骨矿物含量(bone mineral content,BMC),HE染色观察骨组织形态结构。结果去势组血清骨代谢相关生化指标(ALP、BGP、PICP、TRAP)水平较假手术组均显著增高(P0.05),辛伐他汀组、雌二醇组、联合药物组较去势组均降低,尤以联合用药组降低最显著(P0.05)。去势组骨组织BMD和BMC、骨生物力学指标(最大载荷、最大应力、最大位移和刚度)较假手术组显著降低(P0.05),辛伐他汀组、雌二醇组、联合药物组较去势组均增高,尤以联合药物组增高最显著(P0.05)。去势组骨组织骨小梁减少稀疏,排列紊乱,网状结构破坏,大量纤维组织,髓腔内大量空泡状脂肪细胞。联合药物组骨组织结构较完整,骨小梁数目增多,致密均匀粗壮,连接成网状结构,脂肪细胞明显减少。结论辛伐他汀联合雌二醇可调节大鼠骨代谢,增加骨密度和骨矿物质,改善骨生物力学和骨组织形态学,起到抗骨质疏松疗效和骨保护作用。     

降钙素对卵巢切除大鼠股骨骨折愈合的影响

目的观察降钙素对卵巢切除大鼠股骨骨折愈合的作用，为临床上治疗骨质疏松性骨折提供实验依据。方法50只雌性、14周龄SD大鼠共分成5组，每组10只。分成假手术组（Sham，G1），双侧卵巢切除术组（OVX，G2），假手术＋骨折组（Sham＋F，G3），卵巢切除术＋骨折组（OVX＋F，G4），卵巢切除＋骨折＋降钙素药物组（OVX＋F＋CT，G5），骨折组大鼠均采用右股骨中段横行骨折，髓内针固定；降钙素采用皮下给药，隔日1次（16IU·kg^-1）。所有大鼠于术后4周杀死，取右侧股骨标本。然后，分别进行CR摄片、组织形态学观察，并应用双能X线骨密度仪（DEXA）测量右股骨整体、远段和中段骨密度以及BMP-2免疫组化观察，并应用病理图像分析仪对BMP-2免疫组化进行光密度测量。结果（1）OVX组与Sham组比较，BMD显著下降。（2）OVX＋F＋CT组与OVX＋F组比较：骨痂mBMD显著增高；BMP-2的表达无显著性差异。结论降钙素对OVX大鼠股骨骨折具有明显促进骨折愈合的作用，加速编织骨向板层骨的演变过程。