"Melanocytic Nests Arising in Lichenoid Inflammation": Reappraisal of the Terminology "Melanocytic Pseudonests".

Pseudonests or pseudomelanocytic nests represent aggregates of cells and cell fragments, including keratinocytes, macrophages, lymphocytes, and occasional melanocytes. Pseudomelanocytic nests in the setting of lichenoid inflammation can mimic atypical melanocytic proliferations. Several reports documented nonspecific staining of pseudonests with melanoma antigen recognized by T cells-1/Melan-A, which can be detected in the cytoplasm of nonmelanocytic cells. In contrast, nuclear stains, such as MITF and SOX10, avoid this nonmelanocyte cytoplasmic staining. The authors have previously proposed the term melanocytic pseudonests to describe junctional nests with numerous (>2) true melanoma antigen recognized by T cells-1/Melan-A, SOX10, and MITF in a nonmelanocytic lesion with lichenoid inflammation (unilateral lichen planus pigmentosus/erythema dyschromicum perstans). In this study, the authors report another case of this phenomenon arising in a different lichenoid inflammatory dermatitis (lichen planus). The immunophenotype and number of clustered true melanocytes indicate that these dermoepidermal aggregates represent true melanocytic nests and not pseudonests of any type. Therefore, the authors propose the revised terminology of "melanocytic nests arising in lichenoid inflammation" to describe this novel pattern of benign melanocytic reorganization or proliferation in a subset of lichenoid dermatitides. Because this phenomenon can mimic atypical melanocytic proliferations, clinicopathologic correlation is essential for the correct diagnosis.

Remission of refractory benign familial chronic pemphigus (hailey-hailey disease) with the addition of systemic cyclosporine.

BACKGROUND: Benign chronic familial pemphigus (BFCP) is an autosomal dominant dermatosis characterized by flares of painful and often debilitating blistering lesions in high friction areas of the body such as the groin, axillae, lateral neck, and intergluteal cleft. Limited knowledge of its pathophysiology has made treatment of BFCP a considerable challenge and efficacy with current first line therapies, topical corticosteroids and antibiotics, is variable. CASE REPORT: We present a case of this disease in a 52 year old woman that has responded dramatically to the addition of oral cyclosporine to her existing regimen of oral acitretin, with significant improvement of skin lesions, mobility, and quality of life. Cyclosporine's mechanism of action in BFCP is poorly understood, although it possibly acts through inhibition of proinflammatory cytokines in keratinocytes or modulation of intracellular calcium. BFCP, the use of cyclosporine for its treatment, and possible mechanisms of action of cyclosporine are reviewed.

In vivo measurement of human tibial strains during vigorous activity.

Our understanding of mechanical controls on bone remodeling comes from studies of animals with surgically implanted strain gages, but in vivo strain measurements have been made in a single human only once. That study showed that strains in the human tibia during walking and running are well below the fracture threshold. However, strains have never been monitored in vivo during vigorous activity in people, even though prolonged strenuous activity may be responsible for the occurrence of stress fractures. We hypothesized that strains > 3000 microstrain could be produced on the human tibial midshaft during vigorous activity. Strains were measured on the tibiae of two subjects via implanted strain gauges under conditions similar to those experienced by Israeli infantry recruits. Principal compressive and shear strains were greatest for uphill and downhill zigzag running, reaching nearly 2000 microstrain in some cases, about three times higher than recorded during walking. Strain rates were highest during sprinting and downhill running, reaching 0.050/sec. These results show that strain is maintained below 2000 microstrain even under conditions of strenuous activity. Strain rates are higher than previously recorded in human studies, but well within the range reported for running animals.

Gain in mass density of bone following strenuous physical activity.

A group of 223 military recruits aged 18-21 years underwent strenuous physical training for a period of 14 weeks. The absolute bone density of the distal tibia in both lower limbs was measured before the training period and at its end. The density was determined by the Compton scattering technique, which has been developed in our laboratory; this method provides the bone mass of all bone constituents per unit volume. The distribution curve of the bone density in both tibiae shifted to higher values at the end of the training period. The mean bone density in the right and left tibia increased significantly by 7.5%. This study indicates that following an intensive physical exercise regime, a significant increase in the mass density of bone can be obtained in young adults within a short period.

Effect of repletion with dietary calcium on composition and mechanical properties of bone of calcium-deprived rats.

Four groups of rats were fed a low-calcium diet (0.02%) and two groups a normal calcium diet (0.50%). After 2 weeks one group from each dietary calcium level was sacrificed and the femurs examined. The remaining three groups which had been kept on the low-calcium diet were then given diets richer in calcium: 0.25, 0.35 and 0.5%. The remaining group on the normal calcium diet continued receiving it. After two more weeks all animals were sacrificed and their femurs examined. Rats fed the low-calcium diet lagged behind in weight gain; ash content, breaking strength, and modulus of elasticity of their femurs were much lower than those of animals on the normal calcium diet. Feeding diets with increasing calcium content increased bone ash and improved mechanical properties. However, improvement of breaking strength and elasticity did not parallel strictly increases in mineralization. Repletion with a normal calcium diet (0.50%) failed to increase bone ash to normal levels but mechanical properties were improved by repletion with substantially lower dietary calcium levels. Maximal breaking strength was obtained by repletion feeding with a dietary calcium level which failed to increase bone ash. It seems that factors other than mineralization determine breaking strength and elasticity of bone recovering from calcium deprivation.

Effect of intense physical activity on the bone-mineral content in the lower limbs of young adults.

The effect of intense physical training on the bone-mineral content of young adults who are unaccustomed to physical activity has not yet been established. In this study, 268 male recruits, eighteen to twenty-one years old, were evaluated before and after fourteen weeks of strenuous physical training. The bone-mineral content of both legs at the level of the distal third of the tibia in each individual was measured using single-beam photon absorptiometry. The subjects started their training with equal values for bone-mineral content in both legs. During the training period, the average bone-mineral content of the left leg increased by 11.1 per cent and that of the right leg, by 5.2 per cent. In the group of subjects who did not complete the training course, mainly because they incurred stress fractures, the increase in bone-mineral content was significantly less than the increase in those who completed the program. This study indicated that in young adults a high level of loading of bone results in either a stress fracture or a rapid increase in bone-mineral content.

The effect of swimming activity on bone architecture in growing rats.

The effect of non-habitual physical activity on bone architecture in the rat humeral shaft was examined. Two groups of rats were trained to swim for 1 h a day, for 20 weeks, at two training levels. The control group consisted of sedentary rats. Parameters of cross-sectional bone morphology (cross-section areas, principal area moments of inertia and their ratio) were used to evaluate the response of bone architecture to mechanical loading. The strength of bone was assessed by measuring the ultimate compressive force and stress. The cortical cross-section area and principal moments of inertia were found to be significantly higher in the swimming groups than in the controls. Examination of the ratio between the major and minor moments of inertia revealed a pronounced change in the shape of the bone cross-section which became more rounded following swimming training. The ultimate compressive force was significantly higher in the swimming rats while the changes in ultimate stress were not significant. Our results indicate a gain of bone strength due to increased periosteal apposition and modified bone tissue distribution. The marked changes in bone morphology are attributed to the different nature of the forces and moments exerted on the humerus during swimming compared to those prevailing during normal locomotion.

The area moment of inertia of the tibia: a risk factor for stress fractures.

In a prospective study of stress fractures among Israeli infantry recruits, the area moment of inertia of the tibia was found to have a statistically significant correlation with the incidence of tibial, femoral and total stress fractures. Recruits with "low" area moments of inertia of the tibia were found to have higher stress fracture morbidity than those with "high" area moments of inertia. The best correlation was obtained when the area moment of inertia was calculated about the AP axis of bending at a cross-sectional level corresponding to the narrowest tibial width on lateral X-rays, a point which is at the distal quarter of the tibia. This finding indicates that bending forces about the approximate AP axis are an important causal factor for tibial and many other stress fractures. The bone's bending strength, or ability to resist bending moments, as measured by the area moment of inertia, helps determine risk to stress fracture.

The effect of protein malnutrition and nutritional support on the mechanical properties of fracture healing in the injured rat.

We investigated the effect of different nutritional regimens on fracture healing in the injured rat model. Four groups, each consisting of 12 male rats (307 +/- 16 g), were subjected to anesthesia, laparotomy (injury), and tibial osteotomy with internal fixation. Group I received 23% protein, group II received 23% protein and high caloric feed, group III received 5% protein, and group IV received 38% protein. After 8 weeks, calluses were x-rayed and the tibia was removed, fixed in a special block of methyl-metacrylate, and tested at tension up to failure in a mechanical testing apparatus. The distraction force at failure was measured, and callus stiffness and energy absorbed to failure were calculated. The low protein diet resulted in significantly lower tensile strength and stiffness of calluses compared to the other three dietary regimens, this despite adequate caloric intake. In addition, the low protein diet resulted in a callus with "rubbery" mechanical properties compared to the "rigid" calluses of the other three groups. The high protein diet did not result in any significant improvement in fracture healing. These results gain clinical significance in the face of a high incidence of protein calorie malnutrition in injured orthopedic surgery patients.

Optical processing of radiographic trabecular pattern versus bone mineral density of proximal femur as measures of bone strength.

The purpose of the present study was to evaluate a noninvasive method that utilizes optical processing to analyze the trabecular pattern on bone radiographs. The trabecular network on proximal femur radiographs of 17 intact cadaveric femora was analyzed by optical Fourier transform, yielding a trabecular bone index (TBI) at several locations. The bone mineral density (BMD) of the proximal femur was measured by dual X-ray absorptiometry. Dimensions of the proximal femur were obtained from the radiograph. The bones were fractured in a "fall configuration" to yield the fracture load. A multiple regression model, combining only radiograph- derived parameters-bone dimensions and the TBI at the intertrochanteric region and at the greater trochanter-yielded a correlation of 0.938 with the fracture load. A model combining the BMD at the greater trochanter and at the neck yielded a correlation of 0.928 with the fracture load. When all the variables were introduced into a combined analysis, the correlation with the fracture load was 0.973. The TBI obtained by optical processing of the trabecular bone pattern on femoral radiographs together with bone dimensions derived from these radiographs may serve as an effective estimate for hip fracture risk.

In vitro and in situ inhibition of carotenoid biosynthesis in Capsicum annuum by bleaching herbicides.

Pepper leaves treated with the herbicide J852 show an accumulation of phytoene and zeta-carotene, whereas treatment with norflurazon led to an accumulation of only phytoene. The effects of these herbicides were examined in vitro after the expression of carotenoid desaturases in Escherichia coli. Whereas norflurazon is a potent inhibitor of phytoene desaturase (PDS) (I(50) = 0.12 microM) but not of zeta-carotene desaturase (ZDS) (I(50) = 144 microM), J852 inhibits both PDS (I(50) = 23 microM) and ZDS (I(50) = 49 microM). The influence of PDS/ZDS inhibition on gene expression was examined by comparative RT-PCR. None of the examined genes, namely, encoding phytoene synthase, PDS, ZDS, or the terminal oxidase associated with phytoene desaturation, were induced upon herbicide treatment in pepper leaves or seedlings. This was unexpected because inhibition of carotene desaturation led to an up-regulation of the carotenoid biosynthetic capacity (higher amounts of accumulating precursors plus remaining colored carotenoids are present in treated tissues versus control).

Stress fractures. Identifiable risk factors.

To answer the question why such large differences in stress fracture morbidity rates (2% to 64%) exist in different countries, we prospectively evaluated 312 recruits for possible risk factors for stress fractures. Prior to training, each recruit underwent an evaluation including the following: orthopaedic examination, foot and tibial radiographs, measurements of tibial bone width, bone mineral content, bone density, aerobic physical fitness and leg power, assessments of somatotype and smoking habits, and evaluation of sociological and psychological factors. Using a multivariate analysis, two risk factors were identified: recruits with stress fractures had significantly narrower tibiae (P less than 0.001), and a higher degree of external rotation of the hip (P = 0.016). These two variables were independent and cumulative. Stress fracture morbidity was 17%, 29%, and 45% when neither, one, or both risk factors were present, respectively (P less than 0.001). Identification of these risk factors might explain the susceptibility of some people to stress fractures.

Using bone's adaptation ability to lower the incidence of stress fractures.

In three prospective epidemiologic studies of the effect of pre-military-induction sport activities on the incidence of lower extremity stress fractures during infantry basic training, recruits who played ball sports (principally basketball) regularly for at least 2 years before basic training had a significantly lower incidence of stress fractures (13.2%, 16.7%, and 3.6% in the three studies, respectively) than recruits who did not play ball sports (28.9%, 27%, and 18.8%, respectively). Preinduction running was not related to the incidence of stress fracture. To assess the tibial strain environment during these sport activities, we made in vivo strain measurements on three male volunteers from the research team. Peak tibial compression and tension strain and strain rates during basketball reached levels 2 to 5.5 times higher than during walking and about 10% to 50% higher than during running. The high bone strain and strain rates that occurred in recruits while playing basketball in the years before military induction may have increased their bone stiffness, according to Wolff's Law. The stiffer bone could tolerate higher stresses better, resulting in lower strains for a given activity and a lower incidence of stress fractures during basic training.

Youth is a risk factor for stress fracture. A study of 783 infantry recruits.

We report a prospective study of 783 male Israeli recruits aged from 17 to 26 years. The risk of stress fracture was inversely proportional to age on both univariate and multivariate analysis. Each year of increase of age above 17 years reduced the risk of stress fracture by 28%.

Stress fractures and tibial bone width. A risk factor.

A prospective study of 295 infantry recruits has shown that the mediolateral width of the tibia measured radiographically at each of three different levels in the bone had a statistically significant correlation with the total incidence of stress fractures as well as with those in the tibia alone or the femur alone. A narrow tibial width was shown to be a risk factor, but cortical thickness was not found to be significant.

In-vivo strain measurements to evaluate the strengthening potential of exercises on the tibial bone.

Mechanical loading during physical activity produces strains within bones. It is thought that these forces provide the stimulus for the adaptation of bone. Tibial strains and rates of strain were measured in vivo in six subjects during running, stationary bicycling, leg presses and stepping and were compared with those of walking, an activity which has been found to have only a minimal effect on bone mass. Running had a statistically significant higher principal tension, compression and shear strain and strain rates than walking. Stationary bicycling had significantly lower tension and shear strains than walking. If bone strains and/or strain rates higher than walking are needed for tibial bone strengthening, then running is an effective strengthening exercise for tibial bone.

Role of the calcaneal inclination in the energy storage capacity of the human foot--a biomechanical model.

The energy storage capacity of the human foot as a passive structure depends on both its geometry and elastic properties. The present study examines theoretically the relationship between the energy stored in the longitudinal arch and the inclination of the calcaneus, when a vertical load is applied. A simple two-dimensional model was used, consisting of two inclined rigid elements, hinged at the apex of the arch and connected by a horizontal tension spring at the bottom of the arch. The spring serves as the energy-storing element of the model, representing the foot plantar ligaments. The behaviour of the model was examined using both a linear and an exponential spring. It demonstrated that the stored energy depends strongly on the calcaneal inclination. For a given vertical load, the energy storage capacity is low at both large and small inclinations and rises markedly at an intermediate value. Assuming that the incidence of stress fractures during locomotion is affected by insufficient energy attenuation of the foot, this model provides an explanation for the higher prevalence of tibial and femoral stress fractures in subjects with high or low arches.

Interfragmentary lag screws and external fixation for severe open tibial fractures: a biomechanical and clinical study.

The stability offered by the interfragmentary lag screw with a unilateral external fixator frame was studied in both experimental and prospective clinical studies. The in-vitro stability of the fixation with and without the interfragmentary lag screw was tested by a universal testing machine in compression, four-point bending, and torsion in 18 human tibiae. The in-vivo study was conducted prospectively in 18 patients with 19 severe open tibial fractures. All patients were treated with one definite surgical procedure on admission. The interfragmentary lag screw increased the sytem stiffness 47.4 times in compression, 9.9 times in bending, and 3.2 times in torsion. The immediate one-stage care of severe open fractures with a simple external fixation system in combination with the interfragmentary lag screw shortens hospitalization and may enhance healing.

Acoustic emission from trabecular bone during mechanical testing: the effect of osteoporosis and osteoarthritis.

This study examines the relation between the nature of acoustic emission signals emitted from cancellous bone under compression and the mechanical properties of the tissue. The examined bone specimens were taken from 12 normal, 31 osteoporotic and six osteoarthritic femoral heads. The mechanical behaviour of the osteoporotic bone specimens was found to be significantly different from that of the normal specimens both in the pre-yield and post-yield ranges. In the osteoarthritic bones only the elastic behaviour was significantly different. The rates of acoustic events before yield and beyond it were found to be significantly higher both in the osteoporotic and osteoarthritic bone specimens. The average peak amplitude of the signals was also significantly higher in the diseased bones. Stepwise regression analysis showed that a combination of the acoustic emission parameters could significantly predict some mechanical properties of the bone. The energy absorbed during compression and the ultimate compressive stress of the specimens could be estimated from the rate of pre-yield acoustic events, the average amplitude of the signals and the rate of post-yield events. However, the explanation power of the acoustic emission parameters was only moderate. The nature of acoustic emission signals was thus demonstrated to be a potential tool for assessing bone quality.

The effect of shoe sole composition on in vivo tibial strains during walking.

To test the hypothesis that shoe sole composition can affect the level of bone strain and strain rates that contribute to the development of stress fractures, in vivo tibial strain measurements were made during treadmill walking while wearing four shoes which differed only in their sole composition. Soles of 65 Shore A polyurethane with an embedded heel air cell had significantly lower compression and shear strains and shear strain rates than soles of 65, 75 and a composite of 40/65 Shore A polyurethane with no embedded air cells. A sole composed of 65 Shore A polyurethane with an embedded air cell can potentially be protective against stress fracture in a walking shoe.