Case epidemiology from the first three years of a pilot laboratory-based surveillance system for elevated blood-lead concentrations among children in England, 2014-17: implications for public health action.

BACKGROUND: Children incur lead toxicity even at low blood-lead concentrations (BLCs), and testing in England is opportunistic. We described epidemiology of cases notified to a passive laboratory-based surveillance system (SS), the Lead Poisoning in Children (LPIC) SS to inform opportunities to prevent lead exposure in children in England. METHODS: Surveillance population: children <16 years of age and resident in England during the reporting period September 2014-17. Case definition: children with BLC ≥0.48 µmol/l (10 µg/dl). We extracted case demographic/location data and linked it with laboratory, area-level population and socio-economic status (SES) data. We described case BLCs and calculated age-, gender- and SES-specific notification rates, and age-sex standardised regional notification rates. RESULTS: Between 2014 and 2017 there were 86 newly notified cases, giving an annual average notification rate of 2.76 per million children aged 0-15 years. Regionally, rates varied from 0.36 to 9.89 per million. Rates were highest in the most deprived quintile (5.38 per million), males (3.75 per million) and children aged 1-4 years (5.89 per million). CONCLUSIONS: Males, children aged 1-4 years, and children in deprived areas may be at higher risk, and could be targeted for primary prevention. Varied regional notification rates suggest differences in clinician awareness of lead exposure and risk factors; guidelines standardising the indications for BLC-testing may assist secondary prevention.

Changes in blood ion levels after removal of metal-on-metal hip replacements: 16 patients followed for 0-12 months.

BACKGROUND AND PURPOSE: In patients with metal-on-metal (MoM) hip prostheses, pain and joint effusions may be associated with elevated blood levels of cobalt and chromium ions. Since little is known about the kinetics of metal ion clearance from the body and the rate of resolution of elevated blood ion levels, we examined the time course of cobalt and chromium ion levels after revision of MoM hip replacements. PATIENTS AND METHODS: We included 16 patients (13 female) who underwent revision of a painful MoM hip (large diameter, modern bearing) without fracture or infection, and who had a minimum of 4 blood metal ion measurements over an average period of 6.1 (0-12) months after revision. RESULTS: Average blood ion concentrations at the time of revision were 22 ppb for chromium and 43 ppb for cobalt. The change in ion levels after revision surgery varied extensively between patients. In many cases, over the second and third months after revision surgery ion levels decreased to 50% of the values measured at revision. Decay of chromium levels occurred more slowly than decay of cobalt levels, with a 9% lag in return to normal levels. The rate of decay of both metals followed second-order (exponential) kinetics more closely than first-order (linear) kinetics. INTERPRETATION: The elimination of cobalt and chromium from the blood of patients who have undergone revision of painful MoM hip arthroplasties follows an exponential decay curve with a half-life of approximately 50 days. Elevated blood levels of cobalt and chromium ions can persist for at least 1 year after revision, especially in patients with high levels of exposure.

Insufficient acetabular version increases blood metal ion levels after metal-on-metal hip resurfacing.

BACKGROUND: Many factors affect the blood metal ion levels after metal-on-metal (MOM) hip arthroplasty. The main surgically adjustable variable is the amount of coverage of the head provided by the cup which is a function of the inclination and version angles. However, most studies have used plain radiographs which have questionable precision and accuracy, particularly for version and large diameter metal heads; further, these studies do not simultaneously assess version and inclination. Thus the relationship between version and blood metal ions levels has not been resolved. QUESTIONS/PURPOSES: We determined whether cup inclination and version influence blood metal ion levels while adjusting for age at assessment, gender, body mass index, horizontal femoral offset, head size, manufacturer hip type, and Oxford hip score. PATIENTS AND METHODS: We prospectively followed 100 individuals (51 females, 49 males) with unilateral MOM hip resurfacing who underwent clinical assessment, CT scanning, and blood metal ion measurement. Multiple regression analysis was used to determine which variables were predictors of blood metal ion levels and to model the effect of these variables. RESULTS: Only cup inclination, version angles, and gender influenced blood cobalt or chromium levels. Cobalt and chromium levels positively correlated with inclination angle and negatively correlated with version angle. The effect of changes in version angle was less than for inclination angle. Based on our observations, we developed a formula to predict the effect of these parameters on metal ion levels. CONCLUSIONS: Our data suggest insufficient cup version can cause high blood metal ions after MOM hip arthroplasty. We were unable to show that excessive version caused high levels. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Urinary Extracellular Vesicle Protein Profiling and Endogenous Lithium Clearance Support Excessive Renal Sodium Wasting and Water Reabsorption in Thiazide-Induced Hyponatremia.

INTRODUCTION: Thiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC). METHODS: Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry. RESULTS: Analysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients. CONCLUSION: Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before thiazide initiation.

Synchrotron analysis of human organ tissue exposed to implant material.

BACKGROUND: Orthopaedic implants made of cobalt-chromium alloy undergo wear and corrosion that can lead to deposition of cobalt and chromium in vital organs. Elevated cardiac tissue cobalt levels are associated with myocardial injury while chromium is a well-established genotoxin. Though metal composition of tissues surrounding hip implants has been established, few investigators attempted to characterize the metal deposits in systemic tissues of total joint arthroplasty patients. METHODS: We report the first use of micro-X-ray fluorescence coupled with micro-X-ray absorption spectroscopy to probe distribution and chemical form of cobalt, chromium and titanium in postmortem samples of splenic, hepatic and cardiac tissue of patients with metal-on-polyethylene hip implants (n = 5). RESULTS: Majority of the cobalt was in the 2+ oxidation state, while titanium was present exclusively as titanium dioxide, in either rutile or anatase crystal structure. Chromium was found in a range of forms including a highly oxidised, carcinogenic species (CrV/VI), which has never been identified in human tissue before. CONCLUSIONS: Carcinogenic forms of chromium might arise in vital organs of total joint arthroplasty patients. Further studies are warranted with patients with metal-on-metal implants, which tend to have an increased release of cobalt and chromium compared to metal-on-polyethylene hips.

Copper, selenium and zinc levels after bariatric surgery in patients recommended to take multivitamin-mineral supplementation.

BACKGROUND: Bariatric surgery is widely performed to improve obesity-related disorders, but can lead to nutrient deficiencies. In this study we examined serum trace element concentrations before and after bariatric surgery. METHODS: We obtained serum trace element concentrations by inductively coupled plasma-mass spectrometry (ICP-MS) method in 437 patients (82% women, median preoperative body-mass index 46.7 kg/m(2) [interquartile range 42-51]) undergoing either gastric banding (22.7%), sleeve gastrectomy (20.1%), or gastric bypass (57.3%) procedures. Trace element data were available for patients preoperatively (n = 44); and 3 (n = 208), 6 (n = 174), 12 (n = 122), 18 (n = 39), 24 (n = 44) and 36 months (n = 14) post-operatively. All patients were recommended to take a multivitamin-mineral supplement after surgery. RESULTS: Copper deficiency was found in 2% of patients before surgery; and after surgery deficiency rates ranged from 0 to 5% with no significant change in median concentrations during follow-up (p = 0.68). Selenium deficiency was reported in 2% of patients before surgery; and after surgery deficiency rates ranged from 11 to 15% with a near-significant change in median concentrations (p = 0.056). Zinc deficiency was reported in 7% before surgery; and after surgery deficiency rates ranged from 7 to 15% with no significant change in median concentrations (p = 0.39). CONCLUSIONS: In bariatric surgery patients recommended to take multivitamin-mineral supplements, serum copper, zinc and selenium concentrations were mostly stable during the first years after bariatric surgery. There was a possible tendency for selenium concentrations to decline during the early postoperative period.

Evidence for bystander signalling between human trophoblast cells and human embryonic stem cells.

Maternal exposure during pregnancy to toxins can occasionally lead to miscarriage and malformation. It is currently thought that toxins pass through the placental barrier, albeit bi-layered in the first trimester, and damage the fetus directly, albeit at low concentration. Here we examined the responses of human embryonic stem (hES) cells in tissue culture to two metals at low concentration. We compared direct exposures with indirect exposures across a bi-layered model of the placenta cell barrier. Direct exposure caused increased DNA damage without apoptosis or a loss of cell number but with some evidence of altered differentiation. Indirect exposure caused increased DNA damage and apoptosis but without loss of pluripotency. This was not caused by metal ions passing through the barrier. Instead the hES cells responded to signalling molecules (including TNF-α) secreted by the barrier cells. This mechanism was dependent on connexin 43 mediated intercellular 'bystander signalling' both within and between the trophoblast barrier and the hES colonies. These results highlight key differences between direct and indirect exposure of hES cells across a trophoblast barrier to metal toxins. It offers a theoretical possibility that an indirectly mediated toxicity of hES cells might have biological relevance to fetal development.

A long-term assessment of the variability in winter use of dense conifer cover by female white-tailed deer.

BACKGROUND: Long-term studies allow capture of a wide breadth of environmental variability and a broader context within which to maximize our understanding of relationships to specific aspects of wildlife behavior. The goal of our study was to improve our understanding of the biological value of dense conifer cover to deer on winter range relative to snow depth and ambient temperature. METHODOLOGY/PRINCIPAL FINDINGS: We examined variation among deer in their use of dense conifer cover during a 12-year study period as potentially influenced by winter severity and cover availability. Female deer were fitted with a mixture of very high frequency (VHF, n = 267) and Global Positioning System (GPS, n = 24) collars for monitoring use of specific cover types at the population and individual levels, respectively. We developed habitat composites for four study sites. We fit multinomial response models to VHF (daytime) data to describe population-level use patterns as a function of snow depth, ambient temperature, and cover availability. To develop alternative hypotheses regarding expected spatio-temporal patterns in the use of dense conifer cover, we considered two sets of competing sub-hypotheses. The first set addressed whether or not dense conifer cover was limiting on the four study sites. The second set considered four alternative sub-hypotheses regarding the potential influence of snow depth and ambient temperature on space use patterns. Deer use of dense conifer cover increased the most with increasing snow depth and most abruptly on the two sites where it was most available, suggestive of an energy conservation strategy. Deer use of dense cover decreased the most with decreasing temperatures on the sites where it was most available. At all four sites deer made greater daytime use (55 to >80% probability of use) of open vegetation types at the lowest daily minimum temperatures indicating the importance of thermal benefits afforded from increased exposure to solar radiation. Date-time plots of GPS data (24 hr) allowed us to explore individual diurnal and seasonal patterns of habitat use relative to changes in snow depth. There was significant among-animal variability in their propensity to be found in three density classes of conifer cover and other open types, but little difference between diurnal and nocturnal patterns of habitat use. CONCLUSIONS/SIGNIFICANCE: Consistent with our findings reported elsewhere that snow depth has a greater impact on deer survival than ambient temperature, herein our population-level results highlight the importance of dense conifer cover as snow shelter rather than thermal cover. Collectively, our findings suggest that maximizing availability of dense conifer cover in an energetically beneficial arrangement with quality feeding sites should be a prominent component of habitat management for deer.

Zinc, copper, and selenium tissue levels and their relation to subcutaneous abscess, minor surgery, and wound healing in humans.

Trace element involvement in wounds left to heal by secondary intention needs clarification. We have previously reported faster healing of wounds following acute surgery compared with elective excision of pilonidal sinus disease. The effect of topical zinc on the closure of the excisional wounds was mediocre compared with placebo. In contrast, parenteral zinc, copper, and selenium combined appear effective for wound healing in humans. We have investigated zinc, copper, and selenium with respect to (a) impact of acute versus chronic pilonidal sinus and (b) regional concentrations within granulating wounds treated topically with placebo or zinc in 42 (33 males) pilonidal disease patients. Baseline serum and skin concentrations of copper correlated (r S = 0.351, p = 0.033, n = 37), but not of zinc or selenium. Patients with abscesses had elevated serum C-reactive protein (CRP) and copper levels (+29 %; p < 0.001) compared with the elective patients consistent with the strong correlation between serum copper and CRP (r S = 0.715, p < 0.0005, n = 41). Seven days after elective surgery, serum CRP and copper levels were elevated (p = 0.010) versus preoperative values. The copper concentration in wound edges was higher than in periwound skin (p < 0.0005) and wound base (p = 0.010). Selenium levels were increased in wound edge compared to wound base (p = 0.003). Topical zinc oxide treatment doubled (p < 0.050) zinc concentrations in the three tissue localizations without concomitant significant changes of copper or selenium levels. In conclusion, copper and selenium are mobilized to injured sites possibly to enhance host defense and early wound healing mechanisms that are complementary to the necessity of zinc for matrix metalloproteinase activity.

Clinical usefulness of blood metal measurements to assess the failure of metal-on-metal hip implants.

In April 2010, a Medicines and Healthcare Products Regulatory Agency safety alert concerning all metal-on-metal (MOM) hip replacements recommended measuring chromium and cobalt concentrations when managing patients with painful prostheses. The need for this review is illustrated by the recent surge in requests for these blood tests from orthopaedic surgeons following this alert. The aim is to provide guidance to laboratories in assessing these requests and advising clinicians on interpretation. First, we summarize the basic terminology regarding the types of hip replacements, with emphasis on the MOM type. Second, we describe the clinical concerns over implant-derived wear debris in the local tissues and distant sites. Analytical aspects of the measurement of the relevant metal ions and what factors affect the levels measured are discussed. The application of inductively coupled plasma mass spectrometry techniques to the measurement of these metals is considered in detail. The biological effects of metal wear products are summarized with local toxicity and systemic biological effects considered, including carcinogenicity, genotoxicity and systemic toxicity. Clinical cases are used to illustrate pertinent points.

Cobalt from metal-on-metal hip replacements may be the clinically relevant active agent responsible for periprosthetic tissue reactions.

Some types of metal-on-metal (MOM) hip replacements have unacceptably high rates of failure, such as the Ultima TPS MOM hip, with 13.8% failure at 5 years. This has been attributed to an inflammatory reaction following the release of cobalt (Co) and chromium (Cr) from the bearing surfaces and modular junctions. There is in vitro evidence that Co is more important than Cr in the inflammatory process, but there are no reported human tissue studies of the analysis of implant-derived metals.

Winter body condition of moose (Alces alces) in a declining population in northeastern Minnesota.

Assessments of the condition of moose (Alces alces) may be particularly informative to understanding the dynamics of populations and other influential factors. During February-March 2003 to 2005, we assessed the nutritional condition of 79 moose (39 females, 40 males) in northeastern Minnesota by body condition scoring (BCS(F), scale of 0-10); 67 of these by were assessed by ultrasonographic measurements of rump fat (Maxfat), which was used to estimate ingesta-free body fat (IFBF) in all but two of the females. Scores of the BCS(F) were related (r(2)=0.34, P<0.0001) to Maxfat. Body condition scores were not affected by sex × capture-year, capture-year, or age-at-capture, but the mean body condition score of males (6.5 ± 0.2 [SE], n=40) was less (P ≤ 0.009) than that of females (7.4 ± 0.2, n=39). Overall, Maxfat ranged from 0.0 to 4.6 and 0.3 to 2.8 cm in females and males, respectively, and was unaffected by age-at-capture. There was a sex×capture-year effect (P=0.021) on Maxfat; mean values were stable for males during the winters of 2003 to 2005 but in females were lowest during 2003, consistent with the lowest pregnancy rates and lowest winter and spring survival compared to 2004 and 2005. Based on estimates of percent IFBF, late winter-early spring survival in 2003 of at least 11% of the collared animals assessed by Maxfat, 21% of the adult females, specifically, may have been seriously challenged directly by poor condition. Data from this study provide reference values and assessments of body condition of moose that will be an essential component of the additional, comprehensive research needed to better understand the influence of extrinsic and intrinsic factors on the performance of this viable, but declining, population. For future research, we will concentrate on developing a more-reliable BCS which would allow IFBF estimation once rump fat is depleted.

The chemical form of metallic debris in tissues surrounding metal-on-metal hips with unexplained failure.

Implant-derived material from metal-on-metal (MOM) hip arthroplasties may be responsible for an unexplained tissue inflammatory response. The chemical form of the metal species in the tissues is predominantly chromium (Cr), but the currently used techniques have not been able to determine whether this is Cr(III) phosphate or Cr(III) oxide. The analytical challenge must overcome the fact that the metal in the tissues is at a relatively low concentration and tissue preparation or the microscopy beam used can affect the results. Microfocus X-ray spectroscopy using a synchrotron beam is useful in addressing both these issues. Using this technique we compared tissue from failed MOM hips with: (1) tissue from metal-on-polyethylene (MOP) hips; (2) chemical standards; (3) metal discs cut from MOM hips. The most abundant implant-related species in all MOM hip tissues contained Cr. Comparison with standards revealed the chemical form was Cr(III) phosphate, which did not vary with manufacturer type (four types analysed) or level of blood metal ions. Cobalt (Co) and molybdenum (Mo) were occasionally present in areas of high Cr. Co was normally found in a metallic state in the tissue, while Mo was found in an oxidized state. The variety of metallic species may have arisen from corrosion, wear or a combination of both. No evidence of Cr(VI) was seen in the tissues examined.

Copper deficiency myeloneuropathy in a patient with haemachromatosis: a case report.

A 64-year-old British Caucasian man presented with red skin wheals and breathlessness and then developed a progressive neurological syndrome. Investigation revealed hereditary haemachromatosis, porphyria, and a myelodysplastic syndrome. No unifying diagnosis was made, and his neurological symptoms remained unexplained, until further studies revealed an underlying copper deficiency.

Severe anemia and neutropenia associated with hyperzincemia and hypercalprotectinemia.

Calprotectin, also known as the S100A8/A9 or MRP8/14 complex, is a major calcium-binding protein in the cytosol of neutrophils, monocytes, and keratinocytes. It differs from other S100 proteins in its zinc-binding capacity. The authors describe a 4-year-old girl with severe anemia, neutropenia, inflammation, and severe growth failure. Bone marrow examination showed moderate dyserythropoiesis. No hemolysis, iron deficiency, hemoglobinopathies, immunologic diseases, or autoantibodies were detected. Serum levels of copper and ceruloplasmin were within the normal range, although the serum zinc concentration was markedly increased (310 microg/dL). Urinary zinc excretion and erythrocyte zinc concentrations were within the normal range. Family studies showed normal zinc and copper plasma levels. The patient's plasma calprotectin concentration showed a 6,000-fold increase (2,900 mg/L) compared with normal values. The calprotectin concentration is known to be elevated in many inflammatory conditions but is generally below 10 mg/L and thus far below the levels reported in this patient. The authors describe this case as an inborn error of zinc metabolism caused by dysregulation of calprotectin metabolism, which mainly presented with the features of microcytic anemia and inflammation.

Hyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism.

BACKGROUND: Calprotectin (complex of S100A8 and S100A9) is the major calcium and zinc-binding protein of phagocytes. We report a new syndrome with recurrent infections, inflammation, and hyperzincaemia associated with excessively high plasma concentrations of calprotectin. METHODS: We measured calprotectin in plasma and protein fractions by ELISA assay and zinc by atomic absorption spectrometry. Plasma proteins were fractionated by size exclusion chromatography and electrophoresis. Mass spectra of purified proteins were determined by MALDI-TOFMS. FINDINGS: We assessed five patients, two of whom are related. All patients had much the same biochemical findings of hyperzincaemia (77-200 micromol/L, reference range 11-18 micromol/L) and raised plasma calprotectin concentrations (1.4-6.5 g/L, reference range <1 mg/L). All patients presented with recurrent infections, hepatosplenomegaly, anaemia, and evidence of systemic inflammation. Three patients had cutaneous inflammation and three presented in infancy with severe growth failure. Size exclusion chromatography showed that zinc and calprotectin were associated in a broad fraction with molecular weight range 100-300 kDa. Analysis by electrophoresis and mass spectrometry showed that the patients' protein contained normal S100A8 and S100A9 subunits. INTERPRETATION: Dysregulation of zinc metabolism associated with accumulation in plasma of S100A8 and S100A9 defines a new disease, which encompasses a pathological role for dysregulation of two members of the large S100 protein family.