Surveillance results and bone effects in the Gulf War depleted uranium-exposed cohort.

A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored in a clinical surveillance program since 1993. During the spring of 2017, 42 members of the cohort were evaluated with a protocol which includes exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes including measures of bone metabolism, and for participants >50 years, bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained DU shrapnel fragments. Only the mean serum estradiol concentration, a marker of bone metabolism, was found to be significantly different for lower-vs- higher urine U (uU) cohort sub-groups. For the first time, a significant deficit in BMD was observed in the over age 50, high uU sub-group. After more than 25 years since first exposure to DU, an aging cohort of military veterans continues to exhibit few U-related adverse health effects in known target organs of U toxicity. The new finding of reduced BMD in older cohort members, while biologically plausible, was not suggested by other measures of bone metabolism in the full (all ages) cohort, as these were predominantly within normal limits over time. Only estradiol was recently found to display a difference as a function of uU grouping. As BMD is further impacted by aging and the U-burden from fragment absorption accrues in this cohort, a U effect may be clarified in future surveillance visits.

Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes.

BACKGROUND: Lipolysis regulates energy homeostasis through the hydrolysis of intracellular triglycerides and the release of fatty acids for use as energy substrates or lipid mediators in cellular processes. Genes encoding proteins that regulate energy homeostasis through lipolysis are thus likely to play an important role in determining susceptibility to metabolic disorders. METHODS: We sequenced 12 lipolytic-pathway genes in Old Order Amish participants whose fasting serum triglyceride levels were at the extremes of the distribution and identified a novel 19-bp frameshift deletion in exon 9 of LIPE, encoding hormone-sensitive lipase (HSL), a key enzyme for lipolysis. We genotyped the deletion in DNA from 2738 Amish participants and performed association analyses to determine the effects of the deletion on metabolic traits. We also obtained biopsy specimens of abdominal subcutaneous adipose tissue from 2 study participants who were homozygous for the deletion (DD genotype), 10 who were heterozygous (ID genotype), and 7 who were noncarriers (II genotype) for assessment of adipose histologic characteristics, lipolysis, enzyme activity, cytokine release, and messenger RNA (mRNA) and protein levels. RESULTS: Carriers of the mutation had dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes. In adipose tissue from study participants with the DD genotype, the mutation resulted in the absence of HSL protein, small adipocytes, impaired lipolysis, insulin resistance, and inflammation. Transcription factors responsive to peroxisome-proliferator-activated receptor γ (PPAR-γ) and downstream target genes were down-regulated in adipose tissue from participants with the DD genotype, altering the regulation of pathways influencing adipogenesis, insulin sensitivity, and lipid metabolism. CONCLUSIONS: These findings indicate the physiological significance of HSL in adipocyte function and the regulation of systemic lipid and glucose homeostasis and underscore the severe metabolic consequences of impaired lipolysis. (Funded by the National Institutes of Health and others).

Evaluation of human anti-mouse antibody response in normal volunteers following repeated injections of fanolesomab (NeutroSpec), a murine anti-CD15 IgM monoclonal antibody for imaging infection.

BACKGROUND: Fanolesomab (NeutroSpec) is a murine monoclonal Tc labelled anti-CD15 IgM antibody that localizes collections of human polymorphonuclear neutrophils (PMNs) at sites of infection. OBJECTIVES: The objectives of this study were to evaluate the safety of repeated injections of fanolesomab and the extent of induction of human anti-mouse antibody (HAMA) response. METHODS: Thirty healthy adults (15 men and 15 women) were enrolled in the study. Subjects were injected on two separate occasions, separated by 21 days, with 125 microg of fanolesomab that had been labelled with decayed Tc. HAMA assays were performed on blood samples drawn prior to each injection, and at 7 and 28 days following the second injection. Safety was determined by monitoring for adverse events, and for changes in vital signs, physical examination and clinical laboratory measurements. RESULTS: Five subjects exhibited induction of HAMA (16.7%; 95% CI, 6.3-34.2%). Two were considered marginal responses (increase from 5 to 31, and 5 to 20 and 24 ng x ml), and three were considered moderate (7 to 228, 7 to 140 and 270, and 7 to 35 and 450 ng x ml). There were no strong responses (greater than 1000 ng x ml). Seven subjects experienced adverse events, most of which were coincidental to administration of fanolesomab. There were no serious or severe adverse events. CONCLUSIONS: Repeated fanolesomab injections at clinically useful doses does not appear to induce a strong HAMA response nor does it present a risk for serious adverse events.

Comparison of imaging with FDG PET/CT with other imaging modalities in myeloma.

OBJECTIVE: To determine the usefulness of FDG PET/CT scanning in the management and staging of myeloma and to assess its strengths and limitations. DESIGN: FDG PET/CT scans and all other available imaging studies were reviewed retrospectively from 16 consecutive patients by two experienced musculoskeletal radiologists and two nuclear medicine physicians working in consensus. PATIENTS: The 16 patients had undergone a total of 19 FDG PET/CT scans. Radiographs were available in all cases, including 13 skeletal surveys; 25 CT scans (16 chest, three abdominal, four pelvic, one spine, one neck) and 22 MR imaging studies (17 spine, three pelvic, two extremity) also were reviewed. Patients' records were examined for relevant clinical information. All focal areas of abnormal FDG uptake were correlated with the other imaging studies to determine clinical significance. FDG PET/CT scans also were reviewed to see if small lesions shown on the other imaging studies could be identified in retrospect. RESULTS: The 12 men and four women had an average age of 58 years (range 30-69 years). All 16 patients had an established diagnosis of multiple myeloma, with average duration of disease, from time of initial diagnosis to review, of 30 months (range 6 months to 11+ years). The FDG PET/CT scans revealed a total of 104 sites (90 in bone, 14 soft tissue) that were suspicious for neoplastic activity based on a standardized uptake value (SUV) greater than 2.5. Fifty-seven of these sites (55%) were new or previously undetected. The other imaging studies (X-ray, CT, MR) and clinical information confirmed the other 47 areas but also revealed 133 other small skeletal lesions. Six of these 133 additional lesions showed mild FDG uptake on re-review of the PET/CT scans. The FDG PET/CT findings led to management changes in 9/16 patients. MR imaging revealed five cases of diffuse bone involvement (four spine, one scapula) that were not evident by FDG PET/CT. CONCLUSION: FDG PET/CT scans are useful for the management and staging of myeloma. However, if PET/CT were the sole imaging study done, it would miss many additional small lytic skeletal lesions and could miss diffuse spine involvement.