The development of inter-strain variation in cortical and trabecular traits during growth of the mouse lumbar vertebral body.

How cortical and trabecular bone co-develop to establish a mechanically functional structure is not well understood. Comparing early postnatal differences in morphology of lumbar vertebral bodies for three inbred mouse strains identified coordinated changes within and between cortical and trabecular traits. These early coordinate changes defined the phenotypic differences among the inbred mouse strains. INTRODUCTION: Age-related changes in cortical and trabecular traits have been well studied; however, very little is known about how these bone tissues co-develop from day 1 of postnatal growth to establish functional structures by adulthood. In this study, we aimed to establish how cortical and trabecular tissues within the lumbar vertebral body change during growth for three inbred mouse strains that express wide variation in adult bone structure and function. METHODS: Bone traits were quantified for lumbar vertebral bodies of female A/J, C57BL/6J (B6), and C3H/HeJ (C3H) inbred mouse strains from 1 to 105 days of age (n = 6-10 mice/age/strain). RESULTS: Inter-strain differences in external bone size were observed as early as 1 day of age. Reciprocal and rapid changes in the trabecular bone volume fraction and alignment in the direction of axial compression were observed by 7 days of age. Importantly, the inter-strain difference in adult trabecular bone volume fraction was established by 7 days of age. Early variation in external bone size and trabecular architecture was followed by progressive increases in cortical area between 28 and 105 days of age, with the greatest increases in cortical area seen in the mouse strain with the lowest trabecular mass. CONCLUSION: Establishing the temporal changes in bone morphology for three inbred mouse strains revealed that genetic variation in adult trabecular traits were established early in postnatal development. Early variation in trabecular architecture preceded strain-specific increases in cortical area and changes in cortical thickness. This study established the sequence of how cortical and trabecular traits co-develop during growth, which is important for identifying critical early ages to further focus on intervention studies that optimize adult bone strength.

Zoledronate treatment has different effects in mouse strains with contrasting baseline bone mechanical phenotypes.

Two strains of mice with distinct bone morphologies and mechanical properties were treated with zoledronate. Our results show a different response to drug treatment in the two strains providing evidence that baseline properties of structure/material may influence response to zoledronate. INTRODUCTION: Bisphosphonates are highly effective in reducing fracture risk, yet some individuals treated with these agents still experience fracture. The goal of this study was to test the hypothesis that genotype influences the effect of zoledronate on bone mechanical properties. METHODS: Skeletally mature male mice from genetic backgrounds known to have distinct baseline post-yield properties (C57/B6, high post-yield displacement; A/J, low post-yield displacement) were treated for 8 weeks with saline (VEH) or zoledronate (ZOL, 0.06 mg/kg subcutaneously once every 4 weeks) in a 2 × 2 study design. Ex vivo µCT and mechanical testing (4-pt bending) were conducted on the femur to assess morphological and mechanical differences. RESULTS: Significant drug and/or genotype effects were found for several mechanical properties and significant drug × genotype interactions were found for measures of strength (ultimate force) and brittleness (total displacement, strain to failure). Treatment with ZOL affected bone biomechanical measures of brittleness (total displacement (-25 %) and strain to failure (-23 %)) in B6 mice significantly differently than in A/J mice. This was driven by unique drug × genotype effects on bone geometry in B6 animals yet likely also reflected changes to the tissue properties. CONCLUSION: These data may support the concept that properties of the bone geometry and/or tissue at the time of treatment initiation play a role in determining the bone's mechanical response to zoledronate treatment.

Reconstruction of Peri-implant Osseous Defects: A Multicenter Randomized Trial.

There is a paucity of data for the effectiveness of reconstructive procedures in the treatment of peri-implantitis. The objective of this study was to compare reconstruction of peri-implant osseous defects with open flap debridement (OFD) plus porous titanium granules (PTGs) compared with OFD alone. Sixty-three patients (36 female, 27 male; mean age 58.4 y [SD 12.3]), contributing one circumferential peri-implant intraosseous defect, were included in a multinational, multicenter randomized trial using a parallel-group design. After OFD and surface decontamination using titanium brushes and hydrogen peroxide, 33 defects received PTGs. The implants were not submerged. All patients received adjunctive perioperative systemic antibiotics. The primary outcome variable (defect fill) was assessed on digitalized radiographs. Clinical measurements of probing depth (PPD), bleeding on probing (BoP), suppuration, and plaque were taken by blinded examiners. After 12 mo, the test group (OFD plus PTG) showed a mean radiographic defect fill (mesial/distal) of 3.6/3.6 mm compared with 1.1/1.0 in the control group (OFD). Differences were statistically significant in favor of the test group (P < 0.0001). The OFD plus PTG group showed a mean reduction in PPD of 2.8 mm compared with 2.6 mm in the OFD group. BoP was reduced from 89.4% to 33.3% and from 85.8% to 40.4% for the test and control groups, respectively. There was no significant difference in complete resolution of peri-implantitis (PPD ≤4 mm and no BoP at six implant sites and no further bone loss), because this finding was accomplished at 30% of implants in the test group and 23% of implants in the control group. Reconstructive surgery using PTGs resulted in significantly enhanced radiographic defect fill compared with OFD. However, limitations in the lack of ability to discern biomaterial from osseous tissue could not be verified to determine new bone formation. Similar improvements according to clinical measures were obtained after both surgical treatment modalities (ClinicalTrials.gov NCT02406001).

Palliative Surgery for Pseudomyxoma Peritonei.

INTRODUCTION: Pseudomyxoma peritonei is a rare disease causing peritoneal carcinomatosis. In patients with extensive carcinomatosis, curative treatment is unachievable. Palliative debulking therapy is the only treatment in relieving symptoms. We report our results from palliative debulking surgery at a national pseudomyxoma peritonei center in Denmark. METHODS: From January 2007 to October 2012, we performed 27 palliative operations for pseudomyxoma peritonei with debulking at our institution. All patients were evaluated and found eligible for palliative treatment only. Patients were prospectively registered, while perioperative data were collected retrospectively from patient records. RESULTS: The majority of patients (n = 25) received an omentectomy (93%) as the primary procedure. In total, 17 (63%) received additional surgery. Median operative time was 88 min (range: 33-160 min). Median stay at the recovery ward was 6 h (2-288 h). Median hospital stay was 8 days (4-105 days). In all, 23 (85%) patients had no in-hospital complications, whereas 4 patients experienced complications (15%). Two of the complications were mild (Clavien-Dindo grade II), and two experienced severe complications (grade III and IV). Thirty-day mortality was 0%. Median survival was 3.0 years (0.2-6.2 years). CONCLUSION: Palliative debulking is a safe procedure with an acceptable morbidity and mortality offering immediate disease control.

Genetic and epigenetic profiling of CLL disease progression reveals limited somatic evolution and suggests a relationship to memory-cell development.

We examined genetic and epigenetic changes that occur during disease progression from indolent to aggressive forms of chronic lymphocytic leukemia (CLL) using serial samples from 27 patients. Analysis of DNA mutations grouped the leukemia cases into three categories: evolving (26%), expanding (26%) and static (47%). Thus, approximately three-quarters of the CLL cases had little to no genetic subclonal evolution. However, we identified significant recurrent DNA methylation changes during progression at 4752 CpGs enriched for regions near Polycomb 2 repressive complex (PRC2) targets. Progression-associated CpGs near the PRC2 targets undergo methylation changes in the same direction during disease progression as during normal development from naive to memory B cells. Our study shows that CLL progression does not typically occur via subclonal evolution, but that certain CpG sites undergo recurrent methylation changes. Our results suggest CLL progression may involve developmental processes shared in common with the generation of normal memory B cells.

Smaller, weaker, and less stiff bones evolve from changes in subsistence strategy.

UNLABELLED: We propose a computational model with which to examine the evolution of bone. Our results indicate that changes in subsistence strategy have influenced the evolution of bone growth and mechanoregulation, and predict that bone size, stiffness, and structural strength may decrease in future generations, bringing increased risk of fracture and prevalence of osteoporosis. INTRODUCTION: Archeological data suggest that bone size and strength have decreased over evolution. We hypothesize that changing evolutionary pressures and levels of physical activity, both arising from changes in subsistence strategy, have affected the evolution of bone. We propose a computational model with which to examine the evolution of bone growth and mechanoregulation due to the transitions from hunter-gatherer to agricultural to modern lifestyles. METHODS: The evolution of genes governing growth and mechanoregulation in a population of bones is simulated, where each individual is represented by a 2-D bone cross-section. Genetic variability is assumed to modulate growth through mechanoregulatory factors that direct periosteal expansion, endosteal expansion/infilling, and ash content accretion in response to strains incurred during walking. RESULTS: The model predicts decreases in cortical area and section modulus (a measure of structural strength) and increases in maximum compressive strain over the course of the simulation, meaning evolution of smaller, less strong, and less stiff bones is predicted for the population average. The model predicts small but continued decreases in size, strength, and stiffness in modern populations, despite the absence of a strong evolutionary advantage to efficient bones during this phase. CONCLUSION: In conclusion, our results show that changing loading regimes and evolutionary pressures may have influenced the evolution of bone growth and mechanoregulation, and predict that bone size and strength may continue to decrease in future generations, bringing increased risk of fracture and prevalence of osteoporosis.

Activation of bone remodeling after fatigue: differential response to linear microcracks and diffuse damage.

Recent experiments point to two predominant forms of fatigue microdamage in bone: linear microcracks (tens to a few hundred microns in length) and "diffuse damage" (patches of diffuse stain uptake in fatigued bone comprised of clusters of sublamellar-sized cracks). The physiological relevance of diffuse damage in activating bone remodeling is not known. In this study microdamage amount and type were varied to assess whether linear or diffuse microdamage has similar effects on the activation of intracortical resorption. Activation of resorption was correlated to the number of linear microcracks (Cr.Dn) in the bone (R(2)=0.60, p<0.01). In contrast, there was no activation of resorption in response to diffuse microdamage alone. Furthermore, there was no significant change in osteocyte viability in response to diffuse microdamage, suggesting that osteocyte apoptosis, which is known to activate remodeling at typical linear microcracks in bone, does not result from sublamellar damage. These findings indicate that inability of diffuse microdamage to activate resorption may be due to lack of a focal injury response. Finally, we found that duration of loading does not affect the remodeling response. In conclusion, our data indicate that osteocytes activate resorption in response to linear microcracks but not diffuse microdamage, perhaps due to lack of a focal injury-induced apoptotic response.

Genetic variation in the structural pattern of osteoclast activity during post-natal growth of mouse femora.

While the spatial activity of osteoblasts has been associated with modeling of bones during development, few studies have examined if variation in the spatial activity of osteoclasts also contributes to the morphogenesis of skeletal tissues. We examined this question by histomorphometric analysis and reconstructing the three-dimensional spatial distribution of osteoclasts in the femora of three inbred strains of male mice (A/J, C57BL/6J [B6], and C3H/HeJ [C3H]) that have differing skeletal, structural, and material properties. Our data show that total osteoclast surface area and osteoclast numbers are related to the overall bone density, but not related to the development of bone diameter or overall cortical area. The analysis of the spatial distribution of the osteoclasts showed that the asymmetrical mid-diaphyseal distribution of osteoclasts in A/J and B6 compared to the more uniform distribution of these cells around the circumference in the C3H mice was consistent with the more ellipsoid shape of A/J and B6 femora compared to the more circular mid-diaphyseal shape of the femora in the C3H mice. The statistically 2- to 3-fold fewer cells on the periosteal surface in the C3H compared to either the B6 or A/J mice is also consistent with the greater cortical thickness that is seen for the C3H mice compared to either B6 or A/J strains. In vitro studies of osteoclastogenesis and the expression of numerous phenotypic properties of osteoclasts prepared from the three strains of mice showed that A/J and B6 mice developed statistically greater numbers of tartrate resistant acid phosphatase (TRAP) positive cells and expressed statistically higher levels of multiple mRNAs that are unique to differentiated osteoclasts than those isolated from the C3H strain. In summary, the 3D reconstructions and histomorphometric analysis suggest that genetic differences lead to spatial variation in the distribution of osteoclasts. These variations in spatial distribution of osteoclasts in turn contribute in part to the development of the structural variations of the femora that are seen in the three strains of mice. In vitro studies suggest that intrinsic genetic variation in osteoclastogenesis and their phenotypic expression may contribute to the differences in their functional activities that give rise to the unique spatial distributions of these cells in bones.

Osteocyte apoptosis and control of bone resorption following ovariectomy in mice.

INTRODUCTION: Osteocyte apoptosis has been linked to bone resorption resulting from estrogen depletion and other resorptive stimuli; however, precise spatial and temporal relationships between the two events have not been clearly established. The purpose of this study was to characterize the patterns of osteocyte apoptosis in relation to bone resorption following ovariectomy to test whether osteocyte apoptosis occurs preferentially in areas known to activate resorption. Moreover, we report that osteocyte apoptosis is necessary to initiate endocortical remodeling in response to estrogen withdrawal. MATERIALS AND METHODS: Adult female C57BL/6J mice (17 weeks old) underwent either bilateral ovariectomy (OVX), or sham surgery (SHAM) and were euthanized on days 3, 7, 14, or 21 days after OVX. Diaphyseal cross-sections were stained by immunohistochemistry for activated caspase-3 as a marker of apoptosis. The percentages of caspase-positive stained osteocytes (Casp+Ot.) were measured along major and minor anatomical axes around the femoral diaphysis to evaluate the distribution of osteocyte apoptosis after estrogen loss; resorption surface was measured at the adjacent endocortical regions. In a second study to test whether osteocyte apoptosis plays a regulatory role in the initiation of bone resorption, a group of OVX mice received the pan-caspase inhibitor, QVDOPh, to inhibit osteocyte apoptosis. Remaining experimental and sham groups received either QVD or Vehicle. RESULTS: OVX increased osteocyte apoptosis in a non-uniform distribution throughout the femoral diaphyses. Increases in Casp+osteocytes were predominantly located in the posterior diaphyseal cortex. Here, the number of apoptotic osteocytes 4- to 7-fold higher than sham controls (p<0.005) by day 3 post-OVX and remained elevated. Increases in resorption post-OVX also occurred along the posterior endocortical surface overlying the region of osteocyte apoptosis, but these increases occurred only at 14 and 21 days post-OVX (p<0.002) well after the increases in osteocyte apoptosis. Treatment with QVD in OVX animals suppressed osteocyte apoptosis, with levels in QVD-treated samples equivalent to baseline. Moreover, the increases in osteoclastic resorption normally observed after estrogen loss did not occur in OVX mice treated with QVD. CONCLUSIONS: The results of this study demonstrate that osteocyte apoptosis following estrogen loss occur regionally, rather than uniformly throughout the cortex. We also showed that estrogen loss increased osteocyte apoptosis. Apoptotic osteocytes were overwhelmingly localized within the posterior cortical region, the location where endocortical resorption was subsequently activated in ovariectomized mice. Finally, the increases in osteoclastic resorption normally observed after estrogen withdrawal did not occur in the absence of osteocyte apoptosis indicating that this apoptosis is necessary to activate endocortical remodeling following estrogen loss.

Lack of sexual dimorphism in femora of the eusocial and hypogonadic naked mole-rat: a novel animal model for the study of delayed puberty on the skeletal system.

Sex steroid hormones are major determinants of bone morphology and quality and are responsible for sexually dimorphic skeletal traits. Hypogonadism results in suboptimal skeletal development and may lead to an increased risk of bone fracture later in life. The etiology of delayed puberty and/or hypothalamic amenorrhea is poorly understood, and experimental animal models addressing this issue are predominantly based upon short-term experimental induction of hormonal suppression via gonadotropin releasing hormone antagonists (GnRH-a). This acute change in hormone profile does not necessarily emulate the natural progression of hypogonadic bone disorders. We propose a novel animal model with which to explore the effects of chronic hypogonadism on bone quality, the naked mole-rat (NMR; Heterocephalus glaber). This mouse-size rodent may remain reproductively suppressed throughout its life, if it remains as a subordinate within the eusocial mole-rat colony. NMRs live in large colonies with a single dominant breeding female. She, primarily by using aggressive social contact, naturally suppresses the hypothalamic gonadotropic axis of subordinate NMRs and thereby their reproductive expression. However, should an NMR be separated from the dominant breeder, within less than a week reproductive hormones may become elevated and the animal attains breeding status. We questioned if sexual suppression of subordinates impact upon the development and maintenance of the femora and lead to a sexually indistinct monomorphic skeleton. Femora were obtained from male and female NMRs that were either non-breeders (subordinate) or breeders at the time of sacrifice. Diaphyseal cross-sectional morphology, metaphyseal trabecular micro-architecture and tissue mineral density of the femur were measured using microcomputed tomography and diaphyseal mechanical properties were assessed by four-point bending tests to failure. Subordinates were sexually monomorphic and showed no significant differences in body weight or femoral bone structure and quality between males and females. Femora of subordinate females differed significantly from that of breeding animals, whereas in males, the divergent trend among breeders and non-breeders did not reach statistical significance. Subordinate NMRs, naturally suppressed from entering puberty, may prove to be a useful model to tease apart the relationship between bone morphology and hypogonadism and evaluate skeletal development during pubertal maturation.

Experiences with implementation of evidence-based prevention programs to prevent occupational skin diseases in different occupations.

Occupational skin diseases are among the most frequently recognized occupational diseases in many industrialized countries. This paper describes and review experiences with implementation of interventions to prevent occupational skin diseases in different occupational settings representing the food processing industry and a hospital. The study populations were gut cleaners with all participants being exposed to wet work, cheese dairies and a hospital where all employees were included. The effect of implementation of evidence-based prevention programs were tested by questionnaire surveys on baseline and follow-up. A significant reduction in eczema at hands or forearms was observed among gut cleaners. At cheese dairies the eczema frequencies were low except for a comparison dairy where significant changes were seen. At the hospital a non significant reduction in hand eczema was observed. Changes related to use of protective measures and knowledge on prevention of occupational skin diseases were observed. A process evaluation carried out at the gut cleaning departments showed association between the eczema frequency at follow-up, activities related to prevention and implementation of an occupational health management system. In addition to documenting the scientific background for evidence-based prevention programs to prevent occupational skin diseases in different occupations, both the study population and the study design should be considered carefully when testing the implementation of workplace interventions. These aspects may influence the outcome in different directions and either facilitate or hamper the possibilities to provide scientific documentation of the effect of the intervention tested.

A randomised controlled intervention study on prevention of work related skin problems among gut cleaners in swine slaughterhouses.

AIMS: To evaluate the effect of an intervention to reduce work related skin problems in gut cleaning departments in Danish swine slaughterhouses. The intervention consisted of an evidence based prevention programme and a documented method for implementation. METHODS: Randomised controlled intervention study with a one year follow up. The intervention included educational activities and evidence based recommendations. The effect of the intervention was evaluated by telephone interviews using a standardised questionnaire based on the Nordic Occupational Skin Questionnaire (NOSQ-2002) with modified and additional questions on exposure, preventive measures, information, and discussions on prevention of skin problems, etc. RESULTS: A total of 644 (87.5%) responded at the baseline interview and 622 (71.6%) at the one year follow up interview. A total of 495 participated in both interviews (67.3%). In the intervention departments the frequency of eczema on hands or forearms within the past three months at follow up was reduced significantly from 56.2% at baseline to 41.0% at follow up, while a slight non-significant increase was observed in the comparison departments (from 45.9% to 50.2%). The intervention activities resulted in more frequent use of protective gloves in general and the use of cotton gloves worn underneath rubber and plastic gloves. At follow up three times as many in the intervention departments used the recommended high fat skin care products introduced as part of the intervention activities. At follow up, discussion of skin problems was increased in the intervention group while no changes were observed in the comparison group. CONCLUSIONS: A significant 27% relative reduction of occupational eczema in a high risk group was feasible through implementation of an evidence based prevention programme.

The mechanical consequences of mineralization in embryonic bone.

The purpose of this study was to examine the effect of mineralization on the mechanical properties of embryonic bone rudiments. For this purpose, four-point bending experiments were performed on unmineralized and mineralized embryonic mouse ribs at 16 and 17 days of gestational age. Young's modulus was calculated using force-displacement data from the experiment in combination with finite element analysis (FEA). For the unmineralized specimens, a calculated average for the Young's modulus of 1.11 (+/- 0.62) MPa was established after corrections for sticking to the four-point bending device and aspect ratio, which is the ratio between the length of the bone and its diameter. For the mineralized specimens, the value was 117 (+/- 62) MPa after corrections. Hence, Young's moduli of embryonic bone rudiments increase by two orders of magnitude within 1 day, during endochondral ossification. As an effect, the hypertrophic chondrocytes in the calcifying cartilage experience a significant change in their mechanical environment. The chondrocytes are effectively stress shielded, which means that they do not carry stresses since stresses are supported by the stiffest parts of the tissue, which are in this case the diaphyseal cortex and the calcified matrix. The deformability of the hypertrophic chondrocytes is, therefore, severely reduced. Since the transition is so sudden and enormous, it can be seen as a process of 'catastrophic' proportion for the hypertrophic chondrocytes. The subsequent resorption of calcified cartilage and the expansion of the marrow cavity could be consequential to stress shielding.

Monophthalates promote IL-6 and IL-8 production in the human epithelial cell line A549.

The dramatically increasing prevalence of allergic respiratory diseases may in part be due to the presence of certain immunotoxic xenobiotics in the environment. Recent studies have suggested that some plasticizers belonging to the phthalate family, and metabolites thereof, play a role in the development of allergic respiratory diseases. This is probably due to an adjuvant effect, which in some cases may be combined with an inflammatory process. The scope of the present study was to investigate the inflammatory potential of monophthalates, which are degradation products of phthalate plasticizers. The human epithelial cell line A549 was exposed to 15.6-2000 microg/ml, in two-fold dilutions, to either mono-n-butyl phthalate, monobenzyl phthalate, mono-n-octyl phthalate, mono-2-ethylhexyl phthalate, mono-iso-nonyl phthalate or mono-iso-decyl phthalate. Concentrations of the proinflammatory cytokines IL-6 and IL-8 were measured in the cell culture supernatant by ELISA. The study showed that some, but not all, monophthalates could induce a concentration-dependent increase in cytokine production, whereas, at higher concentrations, all phthalates suppressed cytokine production. Both the stimulatory and the suppressive properties were highly dependent on the length of the alkyl side chain of the monophthalate - a structure-activity relationship that is supported by recent observations in mice.

Cyclic hydrostatic pressure enhances the chondrogenic phenotype of human mesenchymal progenitor cells differentiated in vitro.

Much attention has been given to the influences of bioactive factors on mesenchymal progenitor cell differentiation and proliferation, but few studies have examined the effect of mechanical factors on these cells. This study examined the effects of cyclic hydrostatic pressure on human bone marrow-derived mesenchymal progenitor cells undergoing chondrogenic differentiation. Aggregates of bone marrow-derived mesenchymal progenitor cells were cultured in a defined chondrogenic medium and were subjected to cyclic hydrostatic pressure. Aggregates were loaded at various time points: single (day 1 or 3) or multiple (days 1-7). At 14 and 28 days, aggregates were harvested for histology, immunohistochemistry, and quantitative DNA and matrix macromolecule analysis. The aggregates loaded for a single day did not demonstrate significant changes in proteoglycan and collagen contents compared with the non-loaded controls. In contrast, for the multi-day loaded aggregates, statistically significant increases in proteoglycan and collagen contents were found on both day 14 and day 28. Aggregates loaded for seven days were larger and histological staining indicated a greater matrix/cell ratio. This study indicates that hydrostatic pressure enhances the cartilaginous matrix formation of mesenchymal progenitor cells differentiated in vitro, and suggests that mechanical forces may play an important role in cartilage repair and regeneration in vivo.

A lithium clinic for bipolar patients: 2-year outcome of the first 148 patients.

OBJECTIVE: This paper describes the outcome for the first 148 patients referred to a lithium clinic. METHOD: Two-year follow-up data from treatment charts are reported for all patients entering a lithium clinic in the study period. RESULTS: Lithium was given as the only mood stabilizer in 132 (89.2%) of the cases. Thirty-two (21.6%) patients were readmitted with a new affective disorder episode. Twenty-nine (19.6%) patients discontinued treatment prematurely. Variables predicting the recurrence of new affective disorder episodes as well as premature discontinuation of treatment were identified. CONCLUSION: The majority of bipolar patients received lithium for prophylaxis against recurrent affective disorder episodes. The outcome was moderate but comparable to the 30-40% improvement usually reported in follow-up studies of bipolar patients given long-term prophylactic treatment with lithium. Better long-term treatment results for bipolar patients depend on both the development of more effective mood stabilizing drugs or drug combinations and the improvement of patients' adherence to treatment.

Bone brittleness varies with genetic background in A/J and C57BL/6J inbred mice.

The contribution of genetic and environmental factors to variations in bone quality are understood poorly. We tested whether bone brittleness varies with genetic background using the A/J and C57BL/6J inbred mouse strains. Whole bone four-point bending tests revealed a 70% decrease in postyield deflection of A/J femurs compared with C57BL/6J, indicating that A/J femurs failed in a significantly more brittle manner. Cyclic loading studies indicated that A/J femurs accumulated damage differently than C57BL/6J femurs, consistent with their increased brittleness. Differences in matrix composition also were observed between the two mouse strains. A/J femurs had a 4.5% increase in ash content and an 11.8% decrease in collagen content. Interestingly, a reciprocal relationship was observed between femoral geometry and material stiffness; this relationship may have contributed to the brittle phenotype of A/J femurs. A/J femurs are more slender than those of C57BL/6J femurs; however, their 47% smaller moment of inertia appeared to be compensated by an increased tissue stiffness at the expense of altered tissue damageability. Importantly, these differences in whole bone mechanical properties between A/J and C57BL/6J femurs could not have been predicted from bone mass or density measures alone. The results indicated that bone brittleness is a genetically influenced trait and that it is associated with genetically determined differences in whole bone architecture, bone matrix composition, and mechanisms of cyclical damage accumulation.

Effect of impulse duration on patients' perception of electrical stimulation and block effectiveness during axillary block in unsedated ambulatory patients.

BACKGROUND AND OBJECTIVES: Chronaxie of the motor-neurons (A-alpha) is shorter than that of the sensory A-delta and C neurons. Therefore, a short current impulse should elicit a painless muscle twitch. This randomized, double-blind study of patients having ambulatory axillary block by multiple neurostimulations compared patients' perception of electrical stimulation, latency, and quality of analgesia and the incidence of adverse effects. METHODS: In group S (short impulse, n = 44) 0.1-ms-current impulses were used and in group L (long impulse, n = 43) 0.3-ms impulses were used. Initial amplitude was 2 mA. Local anesthetic was injected near the 4 terminal nerves (musculocutaneous, median, ulnar, radial) after reaching a target amplitude between 0.1 and 0.5 mA. Patients were specifically requested to categorize sensation of electrical stimulation "electric shocks" as follows: no discomfort, discomfort, pain. Pain was then quantified on a visual analog scale (VAS). Surgically ineffective blocks were supplemented after 30 minutes. A patient was defined as ready for surgery (complete block) when analgesia was present in all areas distal to the elbow. RESULTS: There were no significant differences between groups in quali- and quantitative assessments of electrical stimulation. Eight patients (18%) in either group described the sensation as "strange or funny." Eight patients in group S and 13 (30%) in group L reported discomfort during stimulation. Twenty-eight patients (64%) in S group and 22 (52%) in L group experienced pain. Median VAS (0 to 100) of this pain was 21 and 24, respectively. Block performance time was 9 minutes in L group and 11 minutes in S group (P < .001), but the latency of analgesia was 23 minutes for both groups and the times to achieve complete block were, therefore, similar: 32 minutes in L group and 34 minutes in S group (not significant [NS]). Nine group S and 8 group L patients required supplementary blocks (NS). The incidence of vessel punctures and accidental intravascular injections were also similar in both groups. CONCLUSIONS: This study did not confirm our hypothesis that short-current impulses (0.1 ms) make neurostimulation of peripheral nerves painless, by selectively depolarizing motor-neurons. Longer impulses (0.3 ms) shorten block performance time, probably by easier location of the nerves, but the clinical relevance of this finding is doubtful.