Risk factors for musculoskeletal-related occupational disability among US Army soldiers.

INTRODUCTION: Minimising temporary and permanent disability associated with musculoskeletal conditions (MSK-D) is critical to the mission of the US Army. Prior research has identified potentially actionable risk factors for overall military disability and its MSK-D subset, including elevated body mass index, tobacco use and physical fitness. However, prior work does not appear to have addressed the impact of these factors on MSK-D when controlling for a full range of factors that may affect health behaviours, including aptitude scores that may serve as a proxy for health literacy. Identifying risk factors for MSK-D when providing control for all such factors may inform efforts to improve military readiness. METHODS: We studied 494 757 enlisted Army soldiers from 2014 to 2017 using a combined medical and administrative database. Leveraging data from the Army's digital 'eProfile' system of duty restriction records, we defined MSK-D as the first restriction associated with musculoskeletal conditions and resulting in the inability to deploy or train. We used multivariable Cox proportional hazards regression to assess the associations between incident MSK-D and selected risk factors including aptitude scores, physical fitness test scores, body mass index and tobacco use. RESULTS: Among the subjects, 281 278 (45.14%) experienced MSK-D. In the MSK-D hazards model, the highest effect size was for failing the physical fitness test (adjusted HR=1.63, 95% CI 1.58 to 1.67, p<0.001) compared with scoring ≥290 points. CONCLUSIONS: The analysis revealed the strongest associations between physical fitness and MSK-D. Additional efforts are warranted to determine potential mechanisms for the observed associations between selected factors and MSK-D.

Comparing functional outcomes in minimally invasive versus open inguinal hernia repair using the army physical fitness test.

PURPOSE: The advantages of minimally invasive inguinal hernia repair (MIHR) over open hernia repair (OHR) continue to be debated. We compared MIHR to OHR by utilizing the Army Physical Fitness Test (APFT) as an outcome measure. METHODS: The APFT is a three-component test scored on a normalized 300 point scale taken semiannually by active-duty military. We identified 1119 patients who met inclusion criteria: 588 in the OHR group and 531 in the MIHR group. Changes in APFT scores, time on post-operative duty restrictions (military profile), and time interval to first post-operative APFT were compared using regression analysis. RESULTS: Postoperatively, no APFT score change difference was observed between the OHR or MIHR groups (- 7.3 ± 30 versus - 5.5 ± 27.7, p = 0.2989). Service members undergoing OHR and MIHR underwent their first post-operative APFT at equal mean timeframes (6.6 ± 5 months versus 6.7 ± 5.1, p = 0.74). No difference was observed for time in months spent on an official temporary duty restriction (military profile) for either OHR or MIHR (0.16 ± 0.16 versus 0.15 ± 0.17, p = 0.311). On adjusted regression analysis, higher pre-operative APFT scores and BMI ≥ 30 were independently associated with reduction in post-operative APFT scores. Higher-baseline APFT scores were independently associated with less time on a post-operative profile, whereas higher BMI (≥ 30) and lower rank were independently associated with longer post-operative profile duration. Higher-baseline APFT scores and lower rank were independently associated with shorter time intervals to the first post-operative APFT. CONCLUSION: Overall, no differences in post-operative APFT scores, military profile time, or time to first post-operative APFT were observed between minimally invasive or open hernioplasty in this military population.

Regional Differences following Partial Salivary Gland Resection.

Regenerative medicine aims to repair, replace, or restore function to tissues damaged by aging, disease, or injury. Partial organ resection is not only a common clinical approach in cancer therapy but also an experimental injury model used to examine mechanisms of regeneration and repair in organs. We performed a partial resection, or partial sialoadenectomy, in the female murine submandibular salivary gland (SMG) to establish a model for investigation of repair mechanisms in salivary glands (SGs). After partial sialoadenectomy, we performed whole-gland measurements over a period of 56 d and found that the gland increased slightly in size. We used microarray analysis and immunohistochemistry (IHC) to examine messenger RNA and protein changes in glands over time. Microarray analysis identified dynamic changes in the transcriptome 3 d after injury that were largely resolved by day 14. At the 3-d time point, we detected gene signatures for cell cycle regulation, inflammatory/repair response, and extracellular matrix (ECM) remodeling in the partially resected glands. Using quantitative IHC, we identified a transient proliferative response throughout the gland. Both secretory epithelial and stromal cells expressed Ki67 that was detectable at day 3 and largely resolved by day 14. IHC also revealed that while most of the gland underwent a wound-healing response that resolved by day 14, a small region of the gland showed an aberrant sustained fibrotic response characterized by increased levels of ECM deposition, sustained Ki67 levels in stromal cells, and a persistent M2 macrophage response through day 56. The partial submandibular salivary gland resection model provides an opportunity to examine a normal healing response and an aberrant fibrotic response within the same gland to uncover mechanisms that prevent wound healing and regeneration in mammals. Understanding regional differences in the wound-healing responses may ultimately affect regenerative therapies for patients.

Mammographic image denoising and enhancement using the Anscombe transformation, adaptive wiener filtering, and the modulation transfer function.

A new restoration methodology is proposed to enhance mammographic images through the improvement of contrast features and the simultaneous suppression of noise. Denoising is performed in the first step using the Anscombe transformation to convert the signal-dependent quantum noise into an approximately signal-independent Gaussian additive noise. In the Anscombe domain, noise is filtered through an adaptive Wiener filter, whose parameters are obtained by considering local image statistics. In the second step, a filter based on the modulation transfer function of the imaging system in the whole radiation field is applied for image enhancement. This methodology can be used as a preprocessing module for computer-aided detection (CAD) systems to improve the performance of breast cancer screening. A preliminary assessment of the restoration algorithm was performed using synthetic images with different levels of quantum noise. Afterward, we evaluated the effect of the preprocessing on the performance of a previously developed CAD system for clustered microcalcification detection in mammographic images. The results from the synthetic images showed an increase of up to 11.5 dB (p = 0.002) in the peak signal-to-noise ratio. Moreover, the mean structural similarity index increased up to 8.3 % (p < 0.001). Regarding CAD performance, the results suggested that the preprocessing increased the detectability of microcalcifications in mammographic images without increasing the false-positive rates. Receiver operating characteristic analysis revealed an average increase of 14.1 % (p = 0.01) in overall CAD performance when restored image sets were used.

PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D.

The small GTPase H-Ras is a proto-oncogene that activates a variety of different pathways including the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway. H-Ras is mutated in many human malignancies, and these mutations cause the protein to be constitutively active. Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) blocks ERK-dependent gene transcription and inhibits proliferation by sequestering ERK in the cytoplasm. We therefore investigated whether PEA-15 influences H-Ras-mediated transformation. We found that PEA-15 does not block H-Ras-activated proliferation when H-Ras is constitutively active. We show instead that in H-Ras-transformed mouse kidney epithelial cells, co-expression of PEA-15 resulted in enhanced soft agar colony growth and increased tumor growth in vivo. Overexpression of both H-Ras and PEA-15 resulted in accelerated G1/S cell cycle transition and increased activation of the ERK signaling pathway. PEA-15 mediated these effects through activation of its binding partner phospholipase D1 (PLD1). Inhibition of PLD1 or interference with PEA-15/PLD1 binding blocked PEA-15's ability to increase ERK activation. Our findings reveal a novel mechanism by which PEA-15 positively regulates Ras/ERK signaling and increases the proliferation of H-Ras-transformed epithelial cells through enhanced PLD1 expression and activation. Thus, our work provides a surprising mechanism by which PEA-15 augments H-Ras-driven transformation. These data reveal that PEA-15 not only suppresses ERK signaling and tumorigenesis but also alternatively enhances tumorigenesis in the context of active Ras.

Ethnic differences in femur geometry in the women's health initiative observational study.

SUMMARY: Participants in the observational study of the Women's Health Initiative (WHI) were studied to determine if ethnic differences in femur geometry can help to explain differences in hip fracture rates. Structural differences in femurs of African and Mexican-American women appear to be consistent with lower rates of hip fractures vs. whites. INTRODUCTION: Ethnic origin has a major influence on hip fractures, but the underlying etiology is unknown. We evaluated ethnic differences in hip fracture rates among 159,579 postmenopausal participants in the WHI then compared femur bone mineral density (BMD) and geometry among a subset with dual X-ray absorptiometry (DXA) scans of the hip and total body. METHODS: The subset included 8,206 non-Hispanic whites, 1,476 African-American (AA), 704 Mexican-American (MA), and 130 Native Americans (NA). Femur geometry derived from hip DXA using hip-structure analysis (HSA) in whites was compared to minority groups after adjustment for age, height, weight, percent lean mass, neck-shaft angle and neck length, hormone use, chronic disease (e.g., diabetes, rheumatoid arthritis, cancer), bone active medications (e.g., corticosteroids, osteoporosis therapies), and clinical center. RESULTS: Both AA and MA women suffered hip fractures at half the rate of whites while NA appeared to be similar to whites. The structural advantage among AA appears to be due to a slightly narrower femur that requires more bone tissue to achieve similar or lower section moduli (SM) vs. whites. This also underlies their higher BMD (reduces region area) and lower buckling ratios (buckling susceptibility). Both MA and NA women had similar advantages vs. whites at the intertrochanter region where cross-sectional area and SM were higher but with no differences at the neck. NA and MA had smaller bending moments vs. whites acting in a fall on the hip (not significant in small NA sample). Buckling ratios of MA did not differ from whites at any region although NA had 4% lower values at the IT region. CONCLUSION: Differences in the geometry at the proximal femur are consistent with the lower hip fracture rates among AA and MA women compared to whites.

Radial bone density and breast cancer risk in white and African-American women.

A number of different models for assessing individual risk of breast cancer use known risk factors such as age, age at menarche, age at first live birth, previous breast biopsies, and family history. High bone mass in white women is also associated with an increased breast cancer risk; however, bone mass as a risk factor has not been studied in African-American women. We conducted a case-control study to evaluate bone mineral density as a risk factor for breast cancer in white and African-American women. We recruited 221 women with newly diagnosed breast cancer from a comprehensive breast cancer center at a large university hospital, and 197 control women who were frequency matched for ethnicity and age. Odds ratios were based on proximal and distal radial bone density measured by peripheral bone densitometry (Norland pDEXA) and expressed as a standardized "Z-score" (age and ethnicity specific). Logistic regression models were fitted controlling for body mass index, menopausal status, age, and HRT use (ever/never and duration). With proximal bone density Z-score included in the model as a continuous variable, a one-unit increase in radial shaft bone density increased the risk of breast cancer by 25% (p=0.02). When proximal bone density Z-score was analyzed as a dichotomous variable (< or = 0, > 0) the odds ratio was 1.98 (95% CI, 1.32 to 2.97); that is, having an above average proximal bone density (age-specific) doubles the risk of breast cancer. There were no significant interactions with, and no appreciable confounding effects by, other covariates. An above-average radial shaft Z-score is a significant risk factor for breast cancer in both white and African-American women. The present study extends the association between bone mass and breast cancer risk to African-Americans, and suggests another potential application for bone density testing.

Whole body bone mass and body composition in a girl with achondroplasia, at ages 9 through 12.

A 9-yr-old white female with achondroplasia was one of a group of 773 children who were recruited for a study of the accumulation of whole body skeletal mass during four annual measurements. Measurements of bone, fat, and lean mass were obtained with a Hologic 1000W instrument. The following variables are used to compare the subject with the 130 healthy white girls who participated in the study: bone mineral content (BMC), bone mineral density (BMD), and bone mineral apparent density (BMAD). Ratios of BMC to weight or BMC to height, and BMD to weight or height, were also calculated. We found that the BMC of the subject was lower when compared to the reference group, but the ratios of BMC to weight or BMC to height were similar in both. BMD was also lower in the patient, but, when expressed in relation to height and weight, the ratios were similar or slightly higher in the case. BMAD was higher in the subject with achondroplasia at all ages. The subject had a lower percentage fat and higher percentage lean mass than the reference children. We conclude that the accumulation of bone mass in this subject with achondroplasia is appropriate for her reduced body size.

Double esterase staining and other neutrophilic granule abnormalities in 237 patients with the myelodysplastic syndrome studied by the cancer and leukemia group B.

We investigated double (specific and nonspecific) esterase (DE) staining in marrow cells of 237 patients with the myelodysplastic syndromes (MDS). Additional abnormalities of neutrophilic granules were examined cytochemically and immunocytochemically for myeloperoxidase activity and antigen elastase, lactoferrin and CD15 granule-membrane glycoproteins. Abnormal DE staining (>/=3% of all nucleated marrow cells) was present in 27% of patients with no difference among different MDS subtypes. However, the prevalence of high abnormal DE staining (>/=10%) was significantly lower in refractory anemia with excess blasts in transformation (1%) compared to other MDS subtypes (12-15%; p = 0.004). The prevalence of other granule abnormalities was not statistically different in the DE normal and DE abnormal groups. Abnormal DE staining is relatively common among all MDS subtypes. High DE staining may identify a subgroup of patients with a lower grade MDS.

Deficiency of neutrophilic granule membrane glycoproteins in the myelodysplastic syndromes: a common deficiency in 216 patients studied by the Cancer and Leukemia Group B.

Previous studies on neutrophils in patients with the myelodysplastic syndromes (MDS) have indicated deficiencies in the contents of primary and secondary granules. However, the granule membrane remains virtually unstudied despite its essential role in the dynamic function of the cytoplasmic granules. In this study, we examined the membrane glycoproteins of primary and secondary granules of peripheral blood and/or bone marrow neutrophils using the monoclonal antibody H36/71 to CD15 glycoproteins. In addition, myeloperoxidase activity and antigen, elastase and lactoferrin were also studied using cytochemical and immunocytochemical stains. A total of 216 patients were included. Deficiencies of granule membrane glycoproteins were the most common, detected in 49%, followed by myeloperoxidase activity (17%), elastase (16%), myeloperoxidase antigen (9%), and lactoferrin (8%). Multiple deficiencies always included granule membrane deficiency. We conclude that granule membrane defects are common in MDS, may provide a common mechanism for multiple granule deficiencies, and may prove to be an additional abnormality associated with granulocyte dysfunction.

Characterization of the mitotic phase pRb-directed protein phosphatase activity.

We have previously reported on the M-phase specific dephosphorylation of pRb and identified a type 1 serine/threonine protein phosphatase (PP1) as the enzyme mediating pRb dephosphorylation. In this report, we have characterized the pRb-directed phosphatase activity found in mitotic cells with respect to dose dependence and demonstrate that the pRb isoform conversion detected in vitro mirrors the pRb isoform conversion which occurs during mitosis of intact cells. Cell fractionation and PP1 catalytic subunit isolation studies support the notion that the pRb-directed phosphatase activity involves subpopulations of PP1 catalytic subunits. Coprecipitation studies revealed that PP1 can form a complex with hypophosphorylated pRb which was converted from the hyperphosphorylated form in mitotic cell extracts. Taken together with data from previous reports in the literature, a model for the regulation of PP1 activity towards pRb during mitotic exit is proposed.

Thermal effects of acrylic cementation at bone tumour sites.

The use of acrylic bone cement as an adjunct to surgical excision of giant cell tumour of bone appears to reduce the incidence of tumour recurrence. Possible mechanisms for this apparent tumour inhibition include cytotoxic effects from the methylmethacrylate monomer and tissue hyperthermia from the heat of polymerization of the cement. This work presents a method for the prediction of temperature fields and resulting tissue necrosis arising from the implantation of polymethylmethacrylate (PMMA) at the site of a curretted giant cell tumour of bone. This is accomplished using a two-dimensional model based on geometry obtained from digitized MRI images of the distal femur. A general-coordinate, non-orthogonal grid generation technique is used and solutions are obtained with an alternating-direction implicit (ADI) finite-difference scheme. The nodal temperature histories are then used to evaluate the effect of variable defect size on the zone of thermally induced cell necrosis. The results suggest the depth of the necrotic region is quite sensitive to the size of the implant. In at least some cases, the heating effect is sufficient to cause significant necrosis of tumorigenic cells. Implanting a large mass of acrylic may risk overkill, damaging substantial amounts of healthy tissue.

High molecular weight protein phosphatase type 1 dephosphorylates the retinoblastoma protein.

pRb controls cell proliferation by restricting inappropriate entry of cells into the cell division cycle. As dephosphorylation of pRb during mitotic exit activates its growth suppressive function, identification of the protein phosphatase that dephosphorylates pRb, and characterization of the mechanism of its regulation, are essential to elucidating the mechanisms of cell growth control. By fractionating mitotic CV-1P cell extracts, we identify the protein phosphatase which dephosphorylates pRb as a type 1 serine/threonine phosphoprotein phosphatase (PP1). Molecular sizing analyses indicate that the catalytic enzyme (PP1c) is present in a high molecular weight complex, with a predicted molecular mass of 166 kDa. PP1-interacting proteins in the mitotic cell extracts are identified. Two PP1-interacting proteins (41 and 110 kDa) are shown to form distinct complexes with PP1c from fractions of separated mitotic cell extracts containing phosphorylase phosphatase activity. However, only the 110-kDa PP1-interacting protein is present in fractions containing pRb-directed phosphatase activity, identifying this protein as a putative activator of PP1 function toward pRb during mitosis.

The high-affinity sulfonylurea receptor: distribution, glycosylation, purification, and immunoprecipitation of two forms from endocrine and neuroendocrine cell lines.

The high-affinity sulfonylurea receptor, a novel member of the ATP-binding cassette superfamily, is one component of the ATP-sensitive K+ channel. The protein is critical for regulation of insulin secretion from pancreatic beta-cells, and mutations in the receptor have been linked to familial hyperinsulinemia, a disorder characterized by unregulated insulin release despite severe hypoglycemia. The sulfonylurea receptor is present in membranes from a number of endocrine and neuroendocrine cell lines, including HIT-T15, RINm5f, alpha TC-6, AtT-20, and GH3 cells. Two forms of the receptor are present in RINm5f and alpha TC-6 cells, with apparent SDS gel molecular masses of 140 and 150 kDa. The two forms have equally high affinity, KD approximately 3 nM, for an iodinated derivative of glyburide, an anti-diabetic sulfonylurea. The receptor is a glycoprotein; treatment of RINm5f or alpha TC-6 cells with tunicamycin reduces the 140 and 150 kDa species to a single approximately 137 kDa protein. The 140 and 150 kDa receptors bind differentially to concanavalin A and wheat germ agglutinin, and lectin-affinity chromatography is ideal for the initial stages of receptor purification. After lectin-affinity chromatography, the same methods can be applied for purifying the 150 kDa form as for the 140 kDa receptor. A transiently expressed receptor with a histidine-tagged carboxy-terminus was purified by Ni-agarose chromatography, and this variant was used to demonstrate that the 140 kDa polypeptide is full length. Anti-peptide antibodies directed against the amino-terminus of the receptor and antibodies against the nucleotide binding folds immunoprecipitate both receptor forms. The results indicate the 140 and 150 kDa receptors are differentially glycosylated forms of the same polypeptide chain.

Control and activity of type-1 serine/threonine protein phosphatase during the cell cycle.

The first part of this discourse will serve as a compendium of selected aspects of PP1 activity and control during the cell cycle. The latter sections will focus on the mammalian cell cycle dependent activity of PP1 on the negative growth regulatory product of the retinoblastoma susceptibility gene, pRB. The purpose here is to suggest one possible mechanism to explain how this phosphatase can effect cell cycle progression. An argument is made for PP1 playing an indirect role in regulating cell cycle progression by modulating the growth suppressive activity of pRB.

Ethnic differences in regional bone density, hip axis length, and lifestyle variables among healthy black and white men.

There are few published data on bone mass, measured by dual-energy X-ray absorptiometry (DXA), in healthy white or black men. Similarly, a recently described predictor of hip fracture among white women, hip axis length (HAL), has not been studied in men. We recruited 160 white and 34 black men, aged 23-80 years, and screened for diseases and drug exposures that adversely affect skeletal health. We measured bone mineral density (BMD) in the lumbar spine, femoral neck, and radial shaft by DXA; height and weight; skin color by reflectometry; and hip axis length both directly from DXA output and using automated software in a subsample. We also obtained historical data on education, smoking, exercise, and fractures. There were no significant black/white differences in mean weight, height, body mass index (BMI), or HAL. The black men had higher BMDs than did the white men at every site (5% for the radius, 10% for the lumbar spine, and 20% for the femoral neck). Skin pigmentation and BMD were not significantly correlated in either group (p > 0.38). Among the white men, smoking was associated with lower lumbar BMD, but there was no significant relationship between BMD and exercise frequency in either group. There was no significant ethnic difference in fracture experience. We conclude that: (1) the higher BMD in black men than in white men is not due to greater body size, (2) the lower hip fracture risk reported for black men than for white men is not due to a difference in hip axis length; (3) skin color is not related to BMD in either sex.