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1.  Longitudinal monitoring of cardiac siderosis using cardiovascular magnetic resonance (CMR) T2* in patients with thalassemia major on various chelation regimens: a 6 year study 
American journal of hematology  2013;88(8):652-656.
Cardiovascular magnetic resonance (CMR) and hepatic magnetic resonance imaging (MRI) has become a reliable non-invasive tool to monitor iron excess in thalassemia major (TM) patients. However, long-term studies are lacking. We reviewed CMR and hepatic MRI T2* imaging on 54 TM patients who had three or more annual measurements. They were managed on various chelation regimens. Patients were grouped according to their degree of cardiac siderosis: severe (T2*<10msec), mild to moderate (T2*=10-20 msec) and no cardiac siderosis (T2*>20msec). We looked at the change in cardiac T2*, liver iron concentration (LIC) and left ventricular ejection fraction (LVEF) at years 3 and 5. In patients with severe cardiac siderosis, cardiac T2* (mean±SD) improved from 6.9±1.6 at baseline to 13.6±10.0 by year 5, mean ΔT2*=6.7 (p-value 0.04). Change in cardiac T2* at year 3 was not significant in the severe group. Patients with mild to moderate cardiac siderosis had mean cardiac T2* of 14.6±2.9 at baseline which improved to 26.3±9.5 by year 3, mean ΔT2*=11.7 (p-value 0.01). At baseline, median LIC (mg/gm dw) in patients with severe, mild-moderate and no cardiac siderosis was 3.6, 2.8 and 3.3 while LVEF (mean±SD) (%) was 56.3±10.1, 60±5 and 66±7.6 respectively. No significant correlation was noted between Δ cardiac T2* and Δ LIC, Δ cardiac T2* and Δ LVEF at years 3 and 5. Throughout the observation period, patients with no cardiac siderosis maintained their cardiac T2* above 20msec. The majority of patients with cardiac siderosis improve cardiac T2* over time with optimal chelation.
PMCID: PMC4030379  PMID: 23640778
thalassemia; cardiac siderosis; chelation
2.  High noon back pain- severe pseudoradicular pain as a lead symptom of superficial siderosis: a case report 
A superficial siderosis of the central nervous system following a traumatic cervical nerve root avulsion usually leads to gait difficulties and hearing loss, whereas back pain is described only rarely. Here we report on the first case with circadian occurrence of severe back pain as the only symptom of a superficial siderosis. We present a case with the most severe pseudoradicular lumbosacral pain occurring daily at noon for the past 5 weeks. The 48-year-old male white patient did not complain of pain in the morning. A traumatic root avulsion 26 years earlier led to a brachial plexus palsy and Horner’s syndrome in this patient. Superficial hemosiderosis in cranial MRI and examination of the cerebrospinal fluid revealing massive red blood cells as well as xanthochromia and elevated protein levels (742 mg/l) led to the diagnosis of a superficial siderosis. A pseudomeningocele caused by a cervical nerve root avulsion is described as a rare reason for superficial siderosis. Surgery on a pseudomeningocele, diagnosed by MRI, led to an immediate disappearance of complaints in our case. Regular neurological investigation and possibly repeated lumbar puncture to exclude superficial siderosis should be considered in cases with severe back pain and a history of traumatic root avulsion. Modern susceptibility weighted MR imaging (SWI) techniques, sensible to the detection of superficial hemosiderosis, might be helpful in the making of a diagnosis.
PMCID: PMC4218875  PMID: 25371709
back pain; pseudoradicular; root avulsion; superficial siderosis
3.  Effects of combined deferiprone with deferoxamine on right ventricular function in thalassaemia major 
Combination therapy with deferoxamine and oral deferiprone is superior to deferoxamine alone in removing cardiac iron and improving left ventricular ejection fraction (LVEF). The right ventricle (RV) is also affected by the toxic effects of iron and may cause additional cardiovascular perturbation. We assessed the effects of combination therapy on the RV in thalassaemia major (TM) using cardiovascular magnetic resonance (CMR).
We retrieved imaging data from 2 treatment trials and re-analyzed the data for the RV responses: Trial 1 was a randomized controlled trial (RCT) of 65 TM patients with mild-moderate cardiac siderosis receiving combination therapy or deferoxamine with placebo; Trial 2 was an open label longitudinal trial assessing combination therapy in 15 TM patients with severe iron loading.
In the RCT, combination therapy with deferoxamine and deferiprone was superior to deferoxamine alone for improving RVEF (3.6 vs 0.7%, p = 0.02). The increase in RVEF was greater with lower baseline T2* 8-12 ms (4.7 vs 0.5%, p = 0.01) than with T2* 12-20 ms (2.2 vs 0.8%, p = 0.47). In patients with severe cardiac siderosis, substantial improvement in RVEF was seen with open-label combination therapy (10.5% ± 5.6%, p < 0.01).
In the RCT of mild to moderate cardiac iron loading, combination treatment improved RV function significantly more than deferoxamine alone. Combination treatment also improved RV function in severe cardiac siderosis. Therefore adding deferiprone to deferoxamine has beneficial effects on both RV and LV function in TM patients with cardiac siderosis.
PMCID: PMC3278357  PMID: 22277065
thalassaemia major; deferiprone; deferoxamine; right ventricular function
4.  Anti-inflammatory activity of nanocrystalline silver-derived solutions in porcine contact dermatitis 
Nanocrystalline silver dressings have anti-inflammatory activity, unlike solutions containing Ag+ only, which may be due to dissolution of multiple silver species. These dressings can only be used to treat surfaces. Thus, silver-containing solutions with nanocrystalline silver properties could be valuable for treating hard-to-dress surfaces and inflammatory conditions of the lungs and bowels. This study tested nanocrystalline silver-derived solutions for anti-inflammatory activity.
Inflammation was induced on porcine backs using dinitrochlorobenzene. Negative and positive controls were treated with distilled water. Experimental groups were treated with solutions generated by dissolving nanocrystalline silver in distilled water adjusted to starting pHs of 4 (using CO2), 5.6 (as is), 7, and 9 (using Ca(OH)2). Solution samples were analyzed for total silver. Daily imaging, biopsying, erythema and oedema scoring, and treatments were performed for three days. Biopsies were processed for histology, immunohistochemistry (for IL-4, IL-8, IL-10, TNF-α, EGF, KGF, KGF-2, and apoptotic cells), and zymography (MMP-2 and -9). One-way ANOVAs with Tukey-Kramer post tests were used for statistical analyses.
Animals treated with pH 7 and 9 solutions showed clear visual improvements. pH 9 solutions resulted in the most significant reductions in erythema and oedema scores. pH 4 and 7 solutions also reduced oedema scores. Histologically, all treatment groups demonstrated enhanced re-epithelialisation, with decreased inflammation. At 24 h, pMMP-2 expression was significantly lowered with pH 5.6 and 9 treatments, as was aMMP-2 expression with pH 9 treatments. In general, treatment with silver-containing solutions resulted in decreased TNF-α and IL-8 expression, with increased IL-4, EGF, KGF, and KGF-2 expression. At 24 h, apoptotic cells were detected mostly in the dermis with pH 4 and 9 treatments, nowhere with pH 5.6, and in both the epidermis and dermis with pH 7. Solution anti-inflammatory activity did not correlate with total silver content, as pH 4 solutions contained significantly more silver than all others.
Nanocrystalline silver-derived solutions appear to have anti-inflammatory/pro-healing activity, particularly with a starting pH of 9. Solutions generated differently may have varying concentrations of different silver species, only some of which are anti-inflammatory. Nanocrystalline silver-derived solutions show promise for a variety of anti-inflammatory treatment applications.
PMCID: PMC2841158  PMID: 20170497
5.  Gradient-echo magnetic resonance imaging study of pancreatic iron overload in young Egyptian beta-thalassemia major patients and effect of splenectomy 
Thalassemic patients suffer from diabetes mellitus secondary to hemosiderosis.
The study aimed to evaluate pancreatic iron overload by T2*-weighted Gradient-echo magnetic resonance imaging (MRI) in young beta-thalassemia major patients and to correlate it with glucose disturbances, hepatic hemosiderosis, serum ferritin and splenectomy.
Forty thalassemic patients (20 non diabetic, 10 diabetic, and 10 with impaired glucose tolerance) were recruited from Pediatric Hematology Clinic, in addition to 20 healthy controls. All patients underwent clinical assessment and laboratory investigations included complete blood count, liver function tests, serum ferritin and oral glucose tolerance test (OGTT). A T2*-weighted gradient-echo sequence MRI was performed with 1.5 T scanner and signal intensity ratio (SIR) of the liver and the pancreas to noise were calculated.
Significant reduction in signal intensity ratio (SIR) of the liver and the pancreas was shown in thalassemic patients compared to controls (P < 0.0001), Thalassemic patients with abnormal glucose tolerance; including diabetics and thalassemics with impaired glucose tolerance; displayed a higher degree of pancreatic and hepatic siderosis compared to thalassemics with normal glucose tolerance or controls (P < 0.001, P < 0.0001). Splenectomized thalassemic patients had significantly lower SIR of pancreas compared to non splenectomized patients (P < 0.05). A strong correlation was present between hepatic and pancreatic siderosis in studied patients (P < 0.001).
pancreatic siderosis can be detected by T2* gradient-echo MRI since childhood in thalassemic patients, and is more evident in patients with abnormal glucose tolerance. After splenectomy, iron deposition may be accelerated in the pancreas. Follow up of thalassemic patients using pancreatic MRI together with intensive chelation therapy may help to prevent the development of overt diabetes.
PMCID: PMC2873247  PMID: 20398341
6.  Superficial Siderosis and Anticoagulation Therapy: Different Presentations, Different Outcomes 
Superficial siderosis is a potentially manageable neurodegenerative disorder, caused by chronic subarachnoid haemorrhage and iron deposition along the central nervous system surfaces. Association with oral anticoagulant therapy is well known, but its definite role as a causative agent is yet to be clarified. Two Caucasian women, both under long-term oral anticoagulation: a 74 year old woman with slowly progressive hearing loss and mild cerebellar ataxia; a 72 year old woman suffering from behavioural changes, rapidly progressive cognitive decline and latter developing paraparesis. Magnetic resonance imaging showed striking hypointensities along the surfaces of cerebellum, brainstem, frontotemporal cortices, spinal cord, and lumbar arachnoid therefore suggesting superficial siderosis. No specific bleeding source was found in any of the patients. Anticoagulation could not be stopped in the first patient due to a mechanic valve and slowly progressive worsening occurred. In contrast, for the second patient anticoagulation withdrawal was feasible and marked motor and cognitive improvement ensued. Superficial siderosis is associated with unvarying progression, mostly when no direct source of bleeding is identified. Nonetheless, we verified striking motor and cognitive improvement after anticoagulants withdrawal in one of the patients. This may reinforce the need to consider such modifiable factor in future patient management.
PMCID: PMC3474227  PMID: 23091751
7.  The cerebral vasculature in dementia pugilistica. 
The brains of 22 ex-boxers were examined histologically to determine the frequency of recent or old haemorrhage. Four boxers had died from an acute intracerebral bleed, usually soon after a boxing bout. Seven of the other 18 showed evidence of previous perivascular haemorrhage, as detected by Perls' ferrocyanide test for iron, and a similar number showed minor degrees of meningeal or subpial siderosis, consistent with previous meningeal bleeding; cerebellar siderosis was present in six cases. Seventeen of the 22 boxers showed evidence of recent or past haemorrhage. Control material showed an incidence of 11% for perivascular iron deposition and only 4% for minor degrees of meningeal siderosis.
PMCID: PMC1032168  PMID: 2732729
8.  Nano-silver in drinking water and drinking water sources: stability and influences on disinfection by-product formation 
Nano-silver is increasingly used in consumer products from washing machines and refrigerators to devices marketed for the disinfection of drinking water or recreational water. The nano-silver in these products may be released, ending up in surface water bodies which may be used as drinking water sources. Little information is available about the stability of the nano-silver in sources of drinking water, its fate during drinking water disinfection processes, and its interaction with disinfection agents and disinfection by-products (DBPs). This study aims to investigate the stability of nano-silver in drinking water sources and in the finished drinking water when chlorine and chloramines are used for disinfection and to observe changes in the composition of DBPs formed when nano-silver is present in the source water. A dispersion of nano-silver particles (10 nm; PVP-coated) was used to spike untreated Ottawa River water, treated Ottawa River water, organic-free water, and a groundwater at concentrations of 5 mg/L. The diluted dispersions were kept under stirred and non-stirred conditions for up to 9 months and analyzed weekly using UV absorption to assess the stability of the nano-silver particles. In a separate experiment, Ottawa River water containing nano-silver particles (at 0.1 and 1 mg/L concentration, respectively) was disinfected by adding sodium hypochlorite (a chlorinating agent) in sufficient amounts to maintain a free chlorine residual of approximately 0.4 mg/L after 24 h. The disinfected drinking water was then quenched with ascorbic acid and analyzed for 34 neutral DBPs (trihalomethanes, haloacetonitriles, haloacetaldehydes, 1,1 dichloro-2-propanone, 1,1,1 trichloro-2-propanone, chloropicrin, and cyanogen chloride). The results were compared to the profile of DBPs obtained under the same conditions in the absence of nano-silver and in the presence of an equivalent concentration of Ag+ ions (as AgNO3). The stability of the nano-silver dispersions in untreated Ottawa River water, with a dissolved organic carbon concentration of 6 mg/L, was significantly higher than the stability of the nano-silver dispersions in distilled, organic-free water. Nano-silver particles suspended in the groundwater agglomerated and were quickly and quantitatively removed from the solution. Our data confirm previous observations that natural dissolved organic matter stabilizes nano-silver particles, while the high-ionic strength of groundwater appears to favor their agglomeration and precipitation. As expected, nano-silver was not stable in Ottawa River water through the chlorination process, but survived for many days when added to the Ottawa River water after treatment with chlorine or chloramines. Stirring appeared to have minimal effect on nano-silver stability in untreated and treated Ottawa River water. The profile of DBPs formed in the presence of nAg differed significantly from the profile of DBPs formed in the absence of nAg only at the 1 mg/L nAg concentration. The differences observed consisted mainly in reduced formation of some brominated DBPs and a small increase in the formation of cyanogen chloride. The reduced formation of brominated congeners may be explained by the decrease in available bromide due to the presence of Ag+ ions. It should be noted that a concentration of 1 mg/L is significantly higher than nAg concentrations that would be expected to be present in surface waters, but these results could be significant for the disinfection of some wastewaters with comparably high nano-silver concentrations.
PMCID: PMC4177100  PMID: 24458938
Nano-silver; Drinking water; Surface water; Chlorination; Disinfection by-products; Stability
9.  On myocardial siderosis and left ventricular dysfunction in hemochromatosis 
Chronically increased intestinal iron uptake in genetic hemochromatosis (HC) may cause organ failure. Whilst iron loading from blood transfusions may cause dilated cardiomyopathy in conditions such as thalassemia, the in-vivo prevalence of myocardial siderosis in HC is unclear, and its relation to left ventricular (LV) dysfunction is controversial. Most previous data on myocardial siderosis in HC has come from post-mortem studies.
Cardiovascular magnetic resonance (CMR) was performed at first presentation of 41 HC patients (58.9 ±14.1 years) to measure myocardial iron and left ventricular (LV) ejection fraction (EF).
In 31 patients (genetically confirmed HFE-HC), the HFE genotype was C282Y/C282Y (n = 30) and C282Y/H63D (n = 1). Patients with other genotypes (n = 10) were labeled genetically unconfirmed HC. Of the genetically confirmed HFE-HC patients, 6 (19%) had myocardial siderosis (T2* <20 ms). Of these, 5 (83%) had heart failure and reduced LVEF which was correlated to the severity of siderosis (R2 0.57, p = 0.049). Two patients had follow-up scans and both had marked improvements in T2* and LVEF following venesection. Myocardial siderosis was present in 6/18 (33%) of patients with presenting ferritin ≥1000 μg/L at diagnosis but in 0/13 (0%) patients with ferritin <1000 μg/L (p = 0.028). Overall however, the relation between myocardial siderosis and ferritin was weak (R2 0.20, p = 0.011). In the 10 genetically unconfirmed HC patients, 1 patient had mild myocardial siderosis but normal EF. Of all 31 patients, 4 had low LVEF from other identifiable causes without myocardial siderosis.
Myocardial siderosis was present in 33% of newly presenting genetically confirmed HFE-HC patients with ferritin >1000 μg/L, and was the commonest cause of reduced LVEF. Heart failure due to myocardial siderosis was only found in these HFE-HC patients, and was reversible with venesection. Myocardial iron was normal in patients with other causes of LV dysfunction.
PMCID: PMC3621377  PMID: 23509881
Iron overload; Heart; Hemochromatosis; Cardiomyopathy; Heart failure; Magnetic resonance
10.  Superficial Siderosis and Sudden Sensorineural Hearing Loss: A Case Report and Review of the Literature 
Case Reports in Otolaryngology  2013;2013:937840.
This case report highlights an unusual case of sudden sensorineural hearing loss related to superficial siderosis (SS). Our patient had a craniotomy for medulloblastoma 23 years earlier, and this may represent a delayed complication related to this procedure. Magnetic resonance imaging (MRI) remains the key diagnostic investigation to illustrate the imaging features of superficial siderosis and exclude other pathologies. Increased awareness of progressive and sudden hearing complications caused by SS is important in the otolaryngologic community to expedite management and better counsel patients during the consent process.
PMCID: PMC3674647  PMID: 23762708
11.  Deferasirox (Exjade®) significantly improves cardiac T2* in heavily iron-overloaded patients with β-thalassemia major 
Annals of Hematology  2009;89(4):405-409.
Noninvasive measurement of tissue iron levels can be assessed using T2* magnetic resonance imaging (MRI) to identify and monitor patients with iron overload. This study monitored cardiac siderosis using T2* MRI in a cohort of 19 heavily iron-overloaded patients with β-thalassemia major receiving iron chelation therapy with deferasirox over an 18-month period. Overall, deferasirox therapy significantly improved mean ± standard deviation cardiac T2* from a baseline of 17.2 ± 10.8 to 21.5 ± 12.8 ms (+25.0%; P = 0.02). A concomitant reduction in median serum ferritin from a baseline of 5,497 to 4,235 ng/mL (−23.0%; P = 0.001), and mean liver iron concentration from 24.2 ± 9.0 to 17.6 ± 12.9 mg Fe/g dry weight (−27.1%; P = 0.01) was also seen. Improvements were seen in patients with various degrees of cardiac siderosis, including those patients with a baseline cardiac T2* of <10 ms, indicative of high cardiac iron burden. These findings therefore support previous observations that deferasirox is effective in the removal of myocardial iron with concomitant reduction in total body iron.
PMCID: PMC2824843  PMID: 19798501
Iron overload; Iron chelation; β-thalassemia; T2* magnetic resonance imaging; Myocardial iron
12.  Superficial siderosis: A rare occurrence in children 
Superficial siderosis of the central nervous system results from deposition of hemosiderin in the subpial layers of the brain and spinal cord. Patients usually present after 40 years of age with progressive ataxia and sensorineural hearing impairment. We present the case of a twelve-year-old boy who had a surgery of the posterior fossa at the age of two years and then developed recurrent headaches, instability of gait, and hearing deficit at around ten years of age. Clinical examination revealed progressive ataxia and mild sensorineural hearing loss. He also had infrequent seizures with mild electroencephalographic abnormality. His serial magnetic resonance imaging (MRIs) showed a progressive deposition of hemosiderin in the cerebellar folia and around the brainstem, confirming a diagnosis of superficial siderosis. This case report draws attention to this rare condition, usually seen in adults, even though rarely it can be seen in children as a chronic sequela of surgery of the posterior fossa.
PMCID: PMC3611915  PMID: 23560013
Hemosiderin; posterior fossa; superficial siderosis
13.  Recurrent craniospinal subarachnoid hemorrhage in cerebral amyloid angiopathy 
Cerebral amyloid angiopathy (CAA) usually manifests as cerebral hemorrhage, especially as nontraumatic hemorrhages in normotensive elderly patients. Other manifestations are subarachnoid (SAH), subdural, intraventricular hemorrhage (IVH) and superficial hemosiderosis. A 52-year-old hypertensive woman presented with recurrent neurological deficits over a period of 2 years. Her serial brain magnetic resonance imaging and computed tomography scans showed recurrent SAH hemorrhage, and also intracerebral, IVH and spinal hemorrhage, with superficial siderosis. Cerebral angiograms were normal. Right frontal lobe biopsy showed features of CAA. CAA can present with unexplained recurrent SAH hemorrhage, and may be the initial and prominent finding in the course of disease in addition to superficial cortical siderosis and intracerebal and spinal hemorrhages.
PMCID: PMC3644794  PMID: 23661974
Amyloid angiopathy; convexity bleeds; subarachnoid hemorrhage; superficial siderosis
14.  Optimal method for early detection of cardiac disorders in thalassemia major patients: magnetic resonance imaging or echocardiography? 
Blood research  2014;49(3):182-186.
Heart failure resulting from myocardial iron deposition is the most important cause of death in β-thalassemia major (TM) patients. Cardiac T2*magnetic resonance imaging (MRI), echocardiography, and serum ferritin level serve as diagnostic methods for detecting myocardial iron overload. In this study, we aimed to evaluate the relationship between the above-mentioned methods.
T2*MRI and echocardiographic measurement of left ventricular (LV) systolic and diastolic function were performed in 63 patients. Serum ferritin level was measured. The relationships between all assessments were evaluated.
There were 40 women and 23 men with a mean age of 23.7±5.1 years (range, 15-35 years). There was no statistically significant correlation between serum ferritin level and LV systolic and diastolic function (P=0.994 and P=0.475, respectively). T2*MRI results had a significant correlation with ferritin level; 63.6% of patients with serum ferritin level >2,000 ng/mL had abnormal cardiac MRI, while none of the patients with ferritin level <1,000 ng/mL had abnormal cardiac MRI (P=0.001). There was no significant correlation between MRI findings and LV systolic function (P=1.00). However, we detected a significant difference between LV diastolic function and cardiac siderosis (P=0.03)
MRI findings are a good predictor of future cardiac dysfunction, even in asymptomatic TM patients; however, diastolic dysfunction may happen prior to cardiac siderosis in some patients, and echocardiography is able to diagnose this diastolic dysfunction while T2*MRI shows normal findings.
PMCID: PMC4188784  PMID: 25325038
Echocardiography; Iron over load; Serum ferritin level; Thalassemia major; T2*MRI
15.  Abnormal deposits of chromium in the pathological human brain. 
Three patients presented with encephalopathies: an undiagnosed degenerative disease of the brain, a degenerative cerebral disease in a patient with a myeloma but without a myelomatous deposit in the CNS and a malignant astrocytoma. Perivascular pallidal deposits (vascular siderosis) containing chromium, phosphorus and calcium plus sometimes traces of other elements were present in the three cases. Such deposits were present in the pallidal parenchyma and around vessels in the cerebellum in one case. Calcium and phosphorus are always present in any CNS calcification but the presence of chromium has not been reported. Chromium and its compounds (ingested, injected or inhaled) are toxic to humans and animals in trace doses. Approximately 900 cases of chromium intoxication have been reported and usually have had dermatological or pulmonary lesions (including cancer) but there is no report of involvement of the CNS. Sublethal doses of chromium nitrate injected intraperitoneally in rats and rabbits results in the presence of chromium in the brain. A thorough investigation was made to find the source of the chromium in these patients. Chromium was found to be present in trace amounts in the radiological contrast agents administered to these patients and in the KCl replacement solution and in mylanta, an antacid, given to one case. The evidence that chromium induced pathological changes in these three brains is circumstantial but shows that chromium can penetrate the human brain. This study indicates that vascular siderosis found in the brains of the majority of middle-aged and elderly humans is not simply an anecdotal pathological curiosity, but that it can serve as a route of entry for toxic products into the brain.
PMCID: PMC1028729  PMID: 3958742
16.  Silver nanoparticle toxicity in Drosophila: size does matter 
Consumer nanotechnology is a growing industry. Silver nanoparticles are the most common nanomaterial added to commercially available products, so understanding the influence that size has on toxicity is integral to the safe use of these new products. This study examined the influence of silver particle size on Drosophila egg development by comparing the toxicity of both nanoscale and conventional-sized silver particles.
The toxicity assays were conducted by exposing Drosophila eggs to particle concentrations ranging from 10 ppm to 100 ppm of silver. Size, chemistry, and agglomeration of the silver particles were evaluated using transmission electron microscopy, X-ray photoelectron spectroscopy, and dynamic light scattering.
This analysis confirmed individual silver particle sizes in the ranges of 20–30 nm, 100 nm, and 500–1200 nm, with similar chemistry. Dynamic light scattering and transmission electron microscope data also indicated agglomeration in water, with the transmission electron microscopic images showing individual particles in the correct size range, but the dynamic light scattering z-average sizes of the silver nanoparticles were 782 ± 379 nm for the 20–30 nm silver nanoparticles, 693 ± 114 nm for the 100 nm silver nanoparticles, and 508 ± 32 nm for the 500–1200 nm silver particles. Most importantly, here we show significantly more Drosophila egg toxicity when exposed to larger, nonnanometer silver particles. Upon exposure to silver nanoparticles sized 20–30 nm, Drosophila eggs did not exhibit a statistically significant (P < 0.05) decrease in their likelihood to pupate, but eggs exposed to larger silver particles (500–1200 nm) were 91% ± 18% less likely to pupate. Exposure to silver nanoparticles reduced the percentage of pupae able to emerge as adults. At 10 ppm of silver particle exposure, only 57% ± 48% of the pupae exposed to 20–30 nm silver particles became adults, whereas 89% ± 25% of the control group became adults, and 94% ± 52% and 91% ± 19% of the 500–1200 nm and 100 nm group, respectively, reached adulthood.
This research provides evidence that nanoscale silver particles (<100 nm) are less toxic to Drosophila eggs than silver particles of conventional (>100 nm) size.
PMCID: PMC3044187  PMID: 21383859
Drosophila; silver; nanoparticle; toxicity
17.  Small changes in lung function in runners with marathon‐induced interstitial lung edema 
Physiological Reports  2014;2(6):e12056.
The purpose of this study was to assess lung function in runners with marathon‐induced lung edema. Thirty‐six (24 males) healthy subjects, 34 (SD 9) years old, body mass index 23.7 (2.6) kg/m2 had posterior/anterior (PA) radiographs taken 1 day before and 21 (6) minutes post marathon finish. Pulmonary function was performed 1–3 weeks before and 73 (27) minutes post finish. The PA radiographs were viewed together, as a set, and evaluated by two experienced readers separately who were blinded as to time the images were obtained. Radiographs were scored for edema based on four different radiological characteristics such that the summed scores for any runner could range from 0 (no edema) to a maximum of 8 (severe interstitial edema). Overall, the mean edema score increased significantly from 0.2 to 1.0 units (P <0.01), and from 0.0 to 2.9 units post exercise in the six subjects that were edema positive (P = 0.03). Despite a 2% decrease in forced vital capacity (FVC, P =0.024) and a 12% decrease in alveolar‐membrane diffusing capacity for carbon monoxide (DmCO, P =0.01), there was no relation between the change in the edema score and the change in DmCO or FVC. In conclusion, (1) mild pulmonary edema occurs in at least 17% of subjects and that changes in pulmonary function cannot predict the occurrence or severity of edema, (2) lung edema is of minimal physiological significance as marathon performance is unaffected, exercise‐induced arterial hypoxemia is unlikely, and postexercise pulmonary function changes are mild.
This study assessed lung function in runners with marathon‐induced interstitial lung edema. Pulmonary function tests and chest radiographs were obtained pre‐ and post marathon finish. Seventeen percent of subjects developed edema but the edema was of minimal physiological importance.
PMCID: PMC4208648  PMID: 24973330
Endurance; exercise; lung fluid; lung function; pulmonary; water
18.  In Vivo Human Time-Exposure Study of Orally Dosed Commercial Silver Nanoparticles 
Nanomedicine : nanotechnology, biology, and medicine  2013;10(1):10.1016/j.nano.2013.06.010.
Human biodistribution, bioprocessing and possible toxicity of nanoscale silver receives increasing health assessment.
We prospectively studied commercial 10- and 32-ppm nanoscale silver particle solutions in a single-blind, controlled, cross-over, intent-to-treat, design. Healthy subjects (n=60) underwent metabolic, blood counts, urinalysis, sputum induction, and chest and abdomen magnetic resonance imaging. Silver serum and urine content was determined.
No clinically important changes in metabolic, hematologic, or urinalysis measures were identified. No morphological changes were detected in the lungs, heart or abdominal organs. No significant changes were noted in pulmonary reactive oxygen species or pro-inflammatory cytokine generation.
In vivo oral exposure to these commercial nanoscale silver particle solutions does not prompt clinically important changes in human metabolic, hematologic, urine, physical findings or imaging morphology. Further study of increasing time exposure and dosing of silver nanoparticulate silver, and observation of additional organ systems is warranted to assert human toxicity thresholds.
PMCID: PMC3877176  PMID: 23811290
biological activity – nanoparticles; nanotechnology; nanotoxicology – oral ingestion; safety research
19.  Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate 
The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials.
AgNPs were synthesized with a size distribution of 14 ± 4 nm in diameter (90% of the nanoparticle volume) and stabilized in aqueous suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the absolute silver concentrations in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concentrations were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallographic (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc.
Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diameter of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver.
The results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver granules containing selenium and sulfur in the intestinal wall of rats exposed to either of the silver forms suggests a common mechanism of their formation. Additional studies however, are needed to gain further insight into the underlying mechanisms of the granule formation, and to clarify whether AgNPs dissolve in the gastrointestinal system and/or become absorbed and translocate as intact nanoparticles to organs and tissues.
PMCID: PMC3123173  PMID: 21631937
20.  PVP-coated, negatively charged silver nanoparticles: A multi-center study of their physicochemical characteristics, cell culture and in vivo experiments 
PVP-capped silver nanoparticles with a diameter of the metallic core of 70 nm, a hydrodynamic diameter of 120 nm and a zeta potential of −20 mV were prepared and investigated with regard to their biological activity. This review summarizes the physicochemical properties (dissolution, protein adsorption, dispersability) of these nanoparticles and the cellular consequences of the exposure of a broad range of biological test systems to this defined type of silver nanoparticles. Silver nanoparticles dissolve in water in the presence of oxygen. In addition, in biological media (i.e., in the presence of proteins) the surface of silver nanoparticles is rapidly coated by a protein corona that influences their physicochemical and biological properties including cellular uptake. Silver nanoparticles are taken up by cell-type specific endocytosis pathways as demonstrated for hMSC, primary T-cells, primary monocytes, and astrocytes. A visualization of particles inside cells is possible by X-ray microscopy, fluorescence microscopy, and combined FIB/SEM analysis. By staining organelles, their localization inside the cell can be additionally determined. While primary brain astrocytes are shown to be fairly tolerant toward silver nanoparticles, silver nanoparticles induce the formation of DNA double-strand-breaks (DSB) and lead to chromosomal aberrations and sister-chromatid exchanges in Chinese hamster fibroblast cell lines (CHO9, K1, V79B). An exposure of rats to silver nanoparticles in vivo induced a moderate pulmonary toxicity, however, only at rather high concentrations. The same was found in precision-cut lung slices of rats in which silver nanoparticles remained mainly at the tissue surface. In a human 3D triple-cell culture model consisting of three cell types (alveolar epithelial cells, macrophages, and dendritic cells), adverse effects were also only found at high silver concentrations. The silver ions that are released from silver nanoparticles may be harmful to skin with disrupted barrier (e.g., wounds) and induce oxidative stress in skin cells (HaCaT). In conclusion, the data obtained on the effects of this well-defined type of silver nanoparticles on various biological systems clearly demonstrate that cell-type specific properties as well as experimental conditions determine the biocompatibility of and the cellular responses to an exposure with silver nanoparticles.
PMCID: PMC4222445  PMID: 25383306
aerosols; biological properties; cell biology; nanoparticles; nanotoxicology; silver
21.  Oxidative stress mediated cytotoxicity of biologically synthesized silver nanoparticles in human lung epithelial adenocarcinoma cell line 
Nanoscale Research Letters  2014;9(1):459.
The goal of the present study was to investigate the toxicity of biologically prepared small size of silver nanoparticles in human lung epithelial adenocarcinoma cells A549. Herein, we describe a facile method for the synthesis of silver nanoparticles by treating the supernatant from a culture of Escherichia coli with silver nitrate. The formation of silver nanoparticles was characterized using various analytical techniques. The results from UV-visible (UV-vis) spectroscopy and X-ray diffraction analysis show a characteristic strong resonance centered at 420 nm and a single crystalline nature, respectively. Fourier transform infrared spectroscopy confirmed the possible bio-molecules responsible for the reduction of silver from silver nitrate into nanoparticles. The particle size analyzer and transmission electron microscopy results suggest that silver nanoparticles are spherical in shape with an average diameter of 15 nm. The results derived from in vitro studies showed a concentration-dependent decrease in cell viability when A549 cells were exposed to silver nanoparticles. This decrease in cell viability corresponded to increased leakage of lactate dehydrogenase (LDH), increased intracellular reactive oxygen species generation (ROS), and decreased mitochondrial transmembrane potential (MTP). Furthermore, uptake and intracellular localization of silver nanoparticles were observed and were accompanied by accumulation of autophagosomes and autolysosomes in A549 cells. The results indicate that silver nanoparticles play a significant role in apoptosis. Interestingly, biologically synthesized silver nanoparticles showed more potent cytotoxicity at the concentrations tested compared to that shown by chemically synthesized silver nanoparticles. Therefore, our results demonstrated that human lung epithelial A549 cells could provide a valuable model to assess the cytotoxicity of silver nanoparticles.
PMCID: PMC4167841  PMID: 25242904
Adenocarcinoma cells A549; Reactive oxygen species generation (ROS); Lactate dehydrogenase (LDH); Mitochondrial transmembrane potential (MTP); Silver nanoparticles (AgNP)
22.  Alveolar-Membrane Diffusing Capacity Limits Performance in Boston Marathon Qualifiers 
PLoS ONE  2012;7(9):e44513.
(1) to examine the relation between pulmonary diffusing capacity and marathon finishing time, and (2), to evaluate the accuracy of pulmonary diffusing capacity for nitric oxide (DLNO) in predicting marathon finishing time relative to that of pulmonary diffusing capacity for carbon monoxide (DLCO).
28 runners [18 males, age = 37 (SD 9) years, body mass = 70 (13) kg, height = 173 (9) cm, percent body fat = 17 (7) %] completed a test battery consisting of measurement of DLNO and DLCO at rest, and a graded exercise test to determine running economy and aerobic capacity prior to the 2011 Steamtown Marathon (Scranton, PA). One to three weeks later, all runners completed the marathon (range: 2∶22:38 to 4∶48:55). Linear regressions determined the relation between finishing time and a variety of anthropometric characteristics, resting lung function variables, and exercise parameters.
In runners meeting Boston Marathon qualification standards, 74% of the variance in marathon finishing time was accounted for by differences in DLNO relative to body surface area (BSA) (SEE = 11.8 min, p<0.01); however, the relation between DLNO or DLCO to finishing time was non-significant in the non-qualifiers (p = 0.14 to 0.46). Whereas both DLCO and DLNO were predictive of finishing time for all finishers, DLNO showed a stronger relation (r2 = 0.30, SEE = 33.4 min, p<0.01) compared to DLCO when considering BSA.
DLNO is a performance-limiting factor in only Boston qualifiers. This suggests that alveolar-capillary membrane conductance is a limitation to performance in faster marathoners. Additionally, DLNO/BSA predicts marathon finishing time and aerobic capacity more accurately than DLCO.
PMCID: PMC3439386  PMID: 22984520
23.  Regional siderosis: a new challenge for iron chelation therapy 
The traditional role of iron chelation therapy has been to reduce body iron burden via chelation of excess metal from organs and fluids and its excretion via biliary-fecal and/or urinary routes. In their present use for hemosiderosis, chelation regimens might not be suitable for treating disorders of iron maldistribution, as those are characterized by toxic islands of siderosis appearing in a background of normal or subnormal iron levels (e.g., sideroblastic anemias, neuro- and cardio-siderosis in Friedreich ataxia- and neurosiderosis in Parkinson's disease). We aimed at clearing local siderosis from aberrant labile metal that promotes oxidative damage, without interfering with essential local functions or with hematological iron-associated properties. For this purpose we introduced a conservative mode of iron chelation of dual activity, one based on scavenging labile metal but also redeploying it to cell acceptors or to physiological transferrin. The “scavenging and redeployment” mode of action was designed both for correcting aberrant iron distribution and also for minimizing/preventing systemic loss of chelated metal. We first examine cell models that recapitulate iron maldistribution and associated dysfunctions identified with Friedreich ataxia and Parkinson's disease and use them to explore the ability of the double-acting agent deferiprone, an orally active chelator, to mediate iron scavenging and redeployment and thereby causing functional improvement. We subsequently evaluate the concept in translational models of disease and finally assess its therapeutic potential in prospective double-blind pilot clinical trials. We claim that any chelator applied to diseases of regional siderosis, cardiac, neuronal or endocrine ought to preserve both systemic and regional iron levels. The proposed deferiprone-based therapy has provided a paradigm for treating regional types of siderosis without affecting hematological parameters and systemic functions.
PMCID: PMC3875873  PMID: 24427136
iron; chelators; sideroblastic anemia; neurodegeneration; Parkinson's disease; Friedereich ataxia
24.  Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction 
In thalassemia major (TM), severe cardiac siderosis can be treated by continuous parenteral deferoxamine, but poor compliance, complications and deaths occur. Combined chelation therapy with deferiprone and deferoxamine is effective for moderate myocardial siderosis, but has not been prospectively examined in severe myocardial siderosis.
T2* cardiovascular magnetic resonance (CMR) was performed in 167 TM patients receiving standard subcutaneous deferoxamine monotherapy, and 22 had severe myocardial siderosis (T2* < 8 ms) with impaired left ventricular (LV) function. Fifteen of these patients received combination therapy with subcutaneous deferoxamine and oral deferiprone with CMR follow-up.
At baseline, deferoxamine was prescribed at 38 ± 10.2 mg/kg for 5.3 days/week, and deferiprone at 73.9 ± 4.0 mg/kg/day. All patients continued both deferiprone and deferoxamine for 12 months. There were no deaths or new cardiovascular complications. The myocardial T2* improved (5.7 ± 0.98 ms to 7.9 ± 2.47 ms; p = 0.010), with concomitant improvement in LV ejection fraction (51.2 ± 10.9% to 65.6 ± 6.7%; p < 0.001). Serum ferritin improved from 2057 (CV 7.6%) to 666 (CV 13.2%) μg/L (p < 0.001), and liver iron improved (liver T2*: 3.7 ± 2.9 ms to 10.8 ± 7.3 ms; p = 0.006).
In patients with severe myocardial siderosis and impaired LV function, combined chelation therapy with subcutaneous deferoxamine and oral deferiprone reduces myocardial iron and improves cardiac function. This treatment is considerably less onerous for the patient than conventional high dose continuous subcutaneous or intravenous deferoxamine monotherapy, and may be considered as an alternative. Very prolonged tailored treatment with iron chelation is necessary to clear myocardial iron, and alterations in chelation must be guided by repeated myocardial T2* scans.
Trial registration
This trial is registered as NCT00103753
PMCID: PMC2289829  PMID: 18298856
25.  Liver iron concentration, stainable iron, and total body storage iron 
Gut  1974;15(5):411-415.
Liver iron concentration has been determined chemically in 154 liver biopsies and the findings compared with the routine histological assessment of stainable parenchymal iron, performed by an independent observer. There was a significant correlation between liver iron concentration and histochemical grading but the relationship did not have a normal linear form. Absence of stainable iron corresponded to liver iron concentrations below the mean value for control male subjects (77 μg/100 mg dry liver). In general grade 1 siderosis corresponded to liver iron concentrations in the upper part of the control range and grade 2 siderosis to marginally elevated values. The transition from grade 2 to grade 3 (submaximal) siderosis represented a sharp increase in liver iron concentration and as grade 3 siderosis corresponded to a wide range of chemical values it is also the most difficult histochemical grade to interpret in quantitative terms. Grade 4 siderosis invariably indicated heavy iron excess.
There was a close correlation between liver iron concentration and measurements of total body storage iron obtained by quantitative phlebotomy in patients with idiopathic haemochromatosis and by determination of DTPA-chelatable body iron in a variety of iron-loading disorders.
PMCID: PMC1412923  PMID: 18668853

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