Early anthropometry, strength, and function in survivors of critical illness.

BACKGROUND: Critically ill patients experience acute muscle wasting and long-term functional impairments, yet this has been inadequately categorised early in recovery. OBJECTIVE: This observational study aimed to evaluate anthropometry, strength, and muscle function after intensive care unit discharge. METHODS: Adult patients able to complete study measures after prolonged intensive care unit stay (≥5 d) were eligible. Demographic and clinical data were collected, and bodyweight, height, triceps skinfold, trunk length, handgrip strength, 6-minute walk test, whole-body dual-energy x-ray absorptiometry, and mid-thigh, knee, and above-ankle circumferences were measured. Body cell mass was calculated from these data. Data are presented as mean (standard deviation) or median [interquartile range]. RESULTS: Fourteen patients (50% male; 57 [10.5] years) were assessed 11.1 (6.9) d after intensive care unit discharge. Patients lost 4.76 (6.66) kg in the intensive care unit. Triceps skinfold thickness (17.00 [8.65] mm) and handgrip strength (12.60 [8.57] kg) were lower than normative data. No patient could commence the 6-minute walk test. Dual-energy x-ray absorptiometry-derived muscle mass correlated with handgrip strength (R = 0.57; 95% confidence interval = 0.06-0.85; p = 0.03), but body cell mass did not. CONCLUSIONS: Anthropometry and strength in intensive care unit survivors are below normal. Muscle mass derived from dual-energy x-ray absorptiometry correlates with handgrip strength but body cell mass does not.

Simulated shift work during pregnancy does not impair progeny metabolic outcomes in sheep.

KEY POINTS: Maternal shift work increases the risk of pregnancy complications, although its effects on progeny health after birth are not clear. We evaluated the impact of a simulated shift work protocol for one-third, two-thirds or all of pregnancy on the metabolic health of sheep progeny. Simulated shift work had no effect on growth, body size, body composition or glucose tolerance in pre-pubertal or young adult progeny. Glucose-stimulated insulin secretion was reduced in adult female progeny and insulin sensitivity was increased in adult female singleton progeny. The results of the present study do not support the hypothesis that maternal shift work exposure impairs metabolic health of progeny in altricial species. ABSTRACT: Disrupted maternal circadian rhythms, such as those experienced during shift work, are associated with impaired progeny metabolism in rodents. The effects of disrupted maternal circadian rhythms on progeny metabolism have not been assessed in altricial, non-litter bearing species. We therefore assessed postnatal growth from birth to adulthood, as well as body composition, glucose tolerance, insulin secretion and insulin sensitivity, in pre-pubertal and young adult progeny of sheep exposed to control conditions (CON: 10 males, 10 females) or to a simulated shift work (SSW) protocol for the first one-third (SSW0-7: 11 males, 9 females), the first two-thirds (SSW0-14: 8 males, 11 females) or all (SSW0-21: 8 males, 13 females) of pregnancy. Progeny growth did not differ between maternal treatments. In pre-pubertal progeny (12-14 weeks of age), adiposity, glucose tolerance and insulin secretion during an i.v. glucose tolerance test and insulin sensitivity did not differ between maternal treatments. Similarly, in young adult progeny (12-14 months of age), food intake, adiposity and glucose tolerance did not differ between maternal treatments. At this age, however, insulin secretion in response to a glucose bolus was 30% lower in female progeny in the combined SSW groups compared to control females (P = 0.031), and insulin sensitivity of SSW0-21 singleton females was 236% compared to that of CON singleton female progeny (P = 0.025). At least in this model, maternal SSW does not impair progeny metabolic health, with some evidence of greater insulin action in female young adult progeny.

Effect of placental restriction and neonatal exendin-4 treatment on postnatal growth, adult body composition, and in vivo glucose metabolism in the sheep.

Intrauterine growth restriction (IUGR) increases the risk of adult type 2 diabetes (T2D) and obesity. Neonatal exendin-4 treatment can prevent diabetes in the IUGR rat, but whether this will be effective in a species where the pancreas is more mature at birth is unknown. Therefore, we evaluated the effects of neonatal exendin-4 administration after experimental restriction of placental and fetal growth on growth and adult metabolic outcomes in sheep. Body composition, glucose tolerance, and insulin secretion and sensitivity were assessed in singleton-born adult sheep from control (CON; n = 6 females and 4 males) and placentally restricted pregnancies (PR; n = 13 females and 7 males) and in sheep from PR pregnancies that were treated with exendin-4 as neonates (daily sc injections of 1 nmol/kg exendin-4; PR + exendin-4; n = 11 females and 7 males). Placental restriction reduced birth weight (by 29%) and impaired glucose tolerance in the adult but did not affect adult adiposity, insulin secretion, or insulin sensitivity. Neonatal exendin-4 suppressed growth during treatment, followed by delayed catchup growth and unchanged adult adiposity. Neonatal exendin-4 partially restored glucose tolerance in PR progeny but did not affect insulin secretion or sensitivity. Although the effects on glucose tolerance are promising, the lack of effects on adult body composition, insulin secretion, and insulin sensitivity suggest that the neonatal period may be too late to fully reprogram the metabolic consequences of IUGR in species that are more mature at birth than rodents.

Heavy metal toxicity of kidney and bone tissues in South Australian adult bottlenose dolphins (Tursiops aduncus).

Metallothioneins (MT) concentration, renal damage, and bone malformations were investigated in 38 adult Tursiops aduncus carcasses to determine any associations with cadmium, copper, zinc, mercury, lead and selenium. Significantly higher concentrations of cadmium, copper, and zinc in the liver were observed in dolphins showing evidence of more advanced renal damage. No significant differences in metal or selenium concentrations in the liver were observed between groups differing in level of bone malformations. Some dolphins displayed evidence of toxicity and knowledge of metal toxicity pathways were used to elucidate the cause of these abnormalities. Two dolphins had high metal burdens, high MT concentrations, renal damage, and evidence of bone malformations, indicating possible severe and prolonged metal toxicity. One dolphin showed evidence of renal damage, but the lack of any other symptoms suggests that this was unlikely to be caused by metal toxicity. We recommend examining a range of metal toxicity symptoms simultaneously to aid in distinguishing metal toxicity from unrelated aetiologies.

Visceral Adipose Tissue Is Associated With Stricturing Crohn's Disease Behavior, Fecal Calprotectin, and Quality of Life.

BACKGROUND: Visceral adipose tissue (VAT) has been proposed to play a pathogenic role in Crohn's disease (CD); however, prospective clinical data are lacking. The aim was to evaluate whether VAT, beyond body mass index (BMI), is associated with CD behavior, disease activity, quality of life (QoL), or outcomes. METHODS: Body composition data and clinical, anthropometric, disease activity (fecal calprotectin [FC]), and QoL scores were gathered prospectively on adults with CD at 0, 12, and 24 months. BMI and, VAT metrics (visceral adipose tissue volume [cm3]/height [m2] index and VAT:subcutaneous adipose tissue [SAT] ratio) were calculated. Inflammatory bowel disease-related surgery and hospitalization were recorded over extended follow-up (median, 51 months). Multivariable linear mixed effects and logistic regression analyses were performed. RESULTS: Ninety-seven participants were assessed at baseline (55% male; median age, 31 years), 84 at 12 months, and 72 at 24 months. VAT:SAT was positively associated with stricturing disease behavior (log odds ratio [OR], 1.7; 95% confidence interval [CI], 0.32 to 3; P = 0.01) and elevated FC in patients with ileocolonic disease (ß, 1.3; 95% CI, 0.32 to 2.3; P = 0.01). VAT:SAT was associated with lower QoL, particularly in those with ileal disease (ß, -12; 95% CI, -19 to -4.5; P = 0.05). However, no prospective associations were observed between serial VAT measurements and time to surgery or hospitalization. No correlations were found between BMI and disease behavior, activity, or QoL. CONCLUSIONS: VAT:SAT, rather than BMI, is associated with stricturing CD behavior, elevated FC, and reduced QoL in a disease distribution-dependent manner. Further studies are required to substantiate the role of VAT as a useful biomarker in CD.

Obesity in Inflammatory Bowel Disease: Gains in Adiposity despite High Prevalence of Myopenia and Osteopenia.

BACKGROUND: Rising rates of obesity have been reported in patients with inflammatory bowel disease (IBD); however, prospective data is lacking. The aim of this study is to prospectively evaluate body composition in adults with IBD over 24 months. METHODS: Whole body dual energy X-ray absorptiometry (DXA) data was performed at 0 months, 12 months, and 24 months. Bone mineral density (BMD), fat mass index (FMI (kg)/height (m²)), appendicular skeletal muscle index (ASMI (kg)/height (m²)), visceral adipose tissue and the visceral adipose height index (VHI, VAT area (cm³)/height (m²)), and clinical and anthropometric assessments were performed at each time point. Multivariable linear mixed effects regression analyses were performed. RESULTS: Initially, 154 participants were assessed at baseline (70% Crohn's disease, 55% male, median age 31 years), of whom 129 underwent repeated DXA at 12 months, and 110 underwent repeated DXA at 24 months. Amongst those undergoing repeated DXA, their body mass index (BMI) significantly increased over time, such that by 24 months, 62% of patients were overweight or obese (annual change BMI ß = 0.43, 95%CI = [0.18, 0.67], p = 0.0006). Gains in BMI related to increases in both FMI and VHI (ß = 0.33, 95%CI = [0.14, 0.53], p = 0.0007; ß = 0.08, 95%CI = [0.02, 0.13], p = 0.001; respectively), whereas ASMI decreased (ß = -0.07, 95%CI = [-0.12, -0.01], p = 0.01) with a concordant rise in rates of myopenia (OR = 3.1 95%CI = [1.2, 7.7]; p = 0.01). Rates of osteopenia and osteoporosis were high (37%), but remained unchanged over time (p = 0.23). CONCLUSION: Increasing rates of obesity in patients with IBD coincide with decreases in lean muscle mass over time, while high rates of osteopenia remain stable. These previously undocumented issues warrant attention in routine care to prevent avoidable morbidity.

Does the response of bone mass to calcium supplements depend on calcium absorption efficiency?

OBJECTIVE: Calcium supplements can reduce bone resorption and slow bone loss after the menopause, but these effects may be limited by poor intestinal absorption. Since the increase in blood ionised calcium and decrease in serum parathyroid hormone after a calcium load are diminished in patients with poor calcium absorption, we aimed to see whether the response of bone mineral content (BMC) to calcium is related to initial calcium absorption. DESIGN: We retrospectively examined the changes in forearm BMC in 164 patients (139 women and 25 men) receiving calcium therapy alone for low bone density in a university hospital. METHODS: BMC was measured in a Molsgaard single energy absorptiometer and calcium absorption in a single blood sample 1 h after a dose of 5 microCi (45)Ca in 20 mg calcium carrier. Results were analysed by simple and multiple regression analysis. RESULTS: Mean forearm BMC did not change significantly over the mean 43 (S.D., 33) months of treatment (1.023 (0.247) to 1.017 (0.246) g/cm). The annual percentage of change was positively related to both body weight (r=0.180; P=0.020) and radiocalcium absorption (r=0.185; P=0.017). Multiple linear regression confirmed that both variables contributed to the change in BMC (P=0.023 and 0.019 respectively). The mean annual percentage of change in BMC on calcium therapy was not related to age, initial BMC, serum 1,25-dihydroxyvitamin D or fasting urinary calcium/creatinine ratio. CONCLUSIONS: These results support our earlier studies which suggest that poor calcium absorption limits the response of bone to calcium supplements.

Liver density measured by DEXA correlates with serum ferritin in patients with beta-Thalassemia Major.

Patients with beta-Thalassemia Major have a requirement for repeated blood transfusion, which ultimately results in liver iron- and whole body iron-overload. These patients are also at risk of reduced bone mineral density (BMD). Seventeen patients (9 female, age 19-32 yr) were referred for bone density estimations of the hip, spine, and whole body. As well as calculating the usual indices of body composition, we superimposed regions of interest over the liver, and expressed the result as "BMD" (g/cm2). This was compared with the serum ferritin as a noninvasive indication of total body iron status. Twelve patients were studied at least twice, more than 18 mo apart. This group showed a significantly below average BMD (T-spine -2.1, T-femoral neck -1.2, T-whole body -1.7, p < 0.001). The group's hepatic density correlated significantly with initial serum ferritin (r = 0.90, p < 0.001). Changes in individual liver density did not correlate significantly with changes in ferritin levels (p = 0.15), possibly due to wide variability in individual results. DEXA may be a useful noninvasive technique for estimating liver-iron concentration.

Recombinant human bone morphogenetic protein-type 2 (rhBMP-2) enhances local bone formation in the lumbar spine of osteoporotic sheep.

The failure of orthopedic implants in osteoporotic patients is attributed to the lack of sufficient bone stock and regenerative capacity but most treatments for osteoporosis fail to address this issue. rhBMP-2 is known to promote bone formation under normal conditions but has not been used clinically in the osteoporotic condition. Osteoporosis was induced in 19 ewes using ovariectomy, low calcium diet, and steroid injection. After induction, the steroid was withdrawn and pellets containing inert carrier with rhBMP-2 in either slow or fast-release formulation were implanted into the lumbar vertebrae of each animal. After 2, 3, and 6 months the spines were harvested and assessed for changes in BMD and histomorphometric indices. BMD did not change after cessation of steroid treatment. After 2 months BV/TV increased in the vicinity of the pellets containing the fast-release rhBMP-2 and was sustained for the duration of the study. Focal voids surrounding all implants, particularly the slow-release formulation, were observed initially but resolved with time. Increased BV/TV adjacent to rhBMP-2 pellets suggests it could be used for localized treatment of osteoporosis. Refinement of the delivery system and supplementary treatments may be necessary to overcome the initial catabolic effects of rhBMP-2.

Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: evidence for site-specific skeletal effects.

CONTEXT: Imatinib is a tyrosine kinase inhibitor that has been successfully used to treat Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Kit(+) gastrointestinal stromal tumors. We have previously shown that imatinib therapy is associated with an increase in trabecular bone volume. OBJECTIVE: In the present study, we performed a prospective analysis of bone indices in imatinib-treated CML patients to determine the mechanism responsible for this altered bone remodeling. DESIGN, PATIENTS, AND INTERVENTION: This study assessed the effects of high-dose (600 mg/d) imatinib on bone parameters in newly diagnosed chronic-phase Philadelphia chromosome-positive CML patients (n = 11) enrolled in the TIDEL II study. At baseline and after 6, 12, and 24 months of treatment, serum markers of bone remodeling were quantitated, dual-energy x-ray absorptiometry analysis of bone mineral density (BMD) was carried out, and a bone biopsy was collected for histological and micro-computed tomography analysis. RESULTS: Our studies show that the increase in trabecular bone volume and trabecular thickness after imatinib treatment was associated with a significant decrease in osteoclast numbers, accompanied by a significant decrease in serum levels of a marker of osteoclast activity. In contrast, osteoblast numbers were not altered by up to 24 months of imatinib treatment. Notably, we also found that imatinib caused a site-specific decrease in BMD at the femoral neck. CONCLUSIONS: These data suggest that imatinib therapy dysregulates bone remodeling, causing a generalized decrease in osteoclast number and activity that is not counterbalanced by a decrease in osteoblast activity, leading to increased trabecular bone volume. Further long-term investigations are required to determine the causes and consequences of the site-specific decrease in BMD at the femoral neck.

Osteoporotic characteristics persist in the spine of ovariectomized sheep after withdrawal of corticosteroid administration.

A validated ovine model of osteoporosis achieves severe bone loss in a relatively short period. This study investigated if osteoporotic features persist in this model after cessation of corticosteroid administration. Methods. Osteoporosis was induced in nine ewes by chronic corticosteroid injection, ovariectomy, and low calcium diet. Six ewes were used as controls. Bone mineral density (BMD) of the lumbar spine (LS) and body weight were assessed at regular intervals. After five months, corticosteroid treatment was withdrawn systematically over one month. Three months later, all animals were euthanised, and the LS was collected for histomorphometric analysis. Results. BMD in the LS of osteoporotic sheep was 25% lower than control sheep. Body weight of osteoporotic sheep was reduced in the first month of the corticosteroid withdrawal period but returned to baseline level thereafter. Trabecular bone volume of LS in osteoporotic sheep was 27% lower than controls and showed a heterogeneous structure. Conclusions. Osteoporotic characteristics remain in the vertebra after ceasing corticosteroid administration providing an opportunity to evaluate potential systemic or local treatments in vivo under realistic physiological conditions. The microstructural arrangement of vertebral trabecular bone in sheep is similar to humans demonstrating further relevance of this model for preclinical investigations.

Measurement of hand bone mineral density in early rheumatoid arthritis using dual energy X-ray absorptiometry.

AIMS: The earliest radiological change in rheumatoid arthritis (RA) is periarticular osteopenia, which occurs prior to the appearance of erosions and clinically apparent deformities. The aim of the study was to measure periarticular bone mineral density (BMD) in the hands of patients with early RA, using dual energy X-ray absorptiomentry (DEXA) and to correlate this with markers of disease activity and radiological progression. METHODS: The study population (n = 50) of patients with RA of < 3 years duration underwent measurement of BMD of the non-dominant hand, femoral neck and lumbar spine and clinical assessment at baseline, 6 and 12 months. Hand radiographs were performed at baseline and 12 months. Thirty age- and sex-matched controls also underwent measurement of BMD of the non-dominant hand, femoral neck and lumbar spine. RESULTS: Hand BMD correlated strongly with sex, height, weight and lumbar and femoral neck BMD in both RA subjects and controls. Baseline hand BMD in RA subjects correlated with baseline serum C-reactive protein (r = -0.36, P = 0.01) and 12-month radiographic score (r = 0.36, P = 0.02). There were small non-significant decreases in hand, femoral neck and lumbar spine BMD over the 12-month period. CONCLUSION: Hand BMD measurement using DEXA is a reproducible, well-tolerated procedure that warrants further investigation as a component of routine assessment in early RA.

Plasma adiponectin levels are markedly elevated in imatinib-treated chronic myeloid leukemia (CML) patients: a mechanism for improved insulin sensitivity in type 2 diabetic CML patients?

CONTEXT: The mechanism(s) by which imatinib improves glycemic control in chronic myeloid leukemia (CML) patients with type 2 diabetes remains unclear. OBJECTIVE: Adiponectin is an important regulator of insulin sensitivity that is secreted exclusively by adipocytes. We previously reported that imatinib promotes adipocytic differentiation of mesenchymal stromal cells. We therefore hypothesized that imatinib therapy would be associated with an increase in peripheral and intramedullary adiposity and elevated plasma adiponectin levels. RESEARCH DESIGN AND METHODS: Adiponectin levels in CML patient plasma, at diagnosis and then during imatinib mesylate therapy, was measured using an ELISA. Adiponectin multimers in plasma were analyzed using nondenaturing PAGE and immunoblotting. Intramedullary adiposity and adipose tissue mass was determined using histomorphometry and dual-energy X-ray absorptiometry, respectively. RESULTS: In CML patients, an increase in intramedullary and peripheral adiposity was observed after 6 months of imatinib therapy and plasma adiponectin levels, in the form of high- and low-molecular-weight complexes, were elevated 3-fold, compared with pretreatment levels, after 3, 6, and 12 months of therapy. CONCLUSIONS: Elevated adiponectin levels in imatinib-treated CML patients provide a possible mechanism for improved glucose and lipid metabolism reported for some imatinib-treated patients.

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo.

Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony-stimulating factor (M-CSF) receptor c-fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c-fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague-Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 microg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole-body bone mineral density and tibial cortical thickness where unchanged in the dasatinib- or ZOL-treated animals relative to controls. However, micro-computed tomographic (microCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib-treated animals at levels comparable with those of the ZOL-treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c-terminal collagen crosslinks (CTX-1). Mineral apposition rate (MAR), bone-formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N-terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib-treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling.