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Iron deficiency anemia is a significant problem in piglets, as they are born with insufficient iron stores for supporting their rapid body growth. Further, sows' milk contains inadequate iron levels for meeting the demands of piglet rapid growth in the pre-wean stage. The forms of iron present in the milk are essential to understanding bioavailability and potential routes for supplementing iron to mitigate iron deficiency anemia in piglets. Recently, our studies showed that H-ferritin (FTH1) is involved in iron transport to different tissues and can be used as an oral iron supplement to correct iron deficiency in rats and monkeys. In this study, we investigate the FTH1 levels in colostrum and milk in Yorkshires-crossbred sows (n = 27) and collected samples at the 1st, 15th, and 28th days of lactation to measure FTH1. Colostrum and milk were found to have FTH1, but there is no significant difference between the different days of lactation. FTH1 has been observed to be enriched in extracellular vesicles (EVs) of other species, and therefore examined the EVs in the samples. Colostrum-derived EVs were enriched with L-ferritin compared to FTH1, while in milk-derived EVs, only FTH1 was detected (P = 0.04). In milk-derived EVs, FTH1 was significantly higher (P = 0.021; P = 006) than FTH1 in colostrum-derived EVs. Furthermore, FTH1 levels of milk-derived EVs were significantly higher (P = 0.0002; P = 0004) than whole milk and colostrum FTH1. These results indicate that FTH1 is enriched in the milk-derived EVs and suggest that EVs play a predominant role in the FTH1 delivery mechanism for the piglet. The extent to which FTH1 in EVs accounts for the overall iron delivery mechanism in piglets is yet to be determined. [ABSTRACT FROM AUTHOR]

Paraquat is an herbicide whose use is associated with Parkinson's disease (PD), a neurodegenerative disorder marked by neuron loss in the substantia nigra pars compacta (SNc). We recently observed that the murine homolog to the human H63D variant of the homeostatic iron regulator (HFE) may decrease paraquat-associated nigral neurotoxicity in mice. The present study examined the potential influence of H63D on paraquat-associated neurotoxicity in humans. Twenty-eight paraquat-exposed workers were identified from exposure histories and compared with 41 unexposed controls. HFE genotypes, and serum iron and transferrin were measured from blood samples. MRI was used to assess the SNc transverse relaxation rate (R2*), a marker for iron, and diffusion tensor imaging scalars of fractional anisotropy (FA) and mean diffusivity, markers of microstructural integrity. Twenty-seven subjects (9 exposed and 18 controls) were H63D heterozygous. After adjusting for age and use of other PD-associated pesticides and solvents, serum iron and transferrin were higher in exposed H63D carriers than in unexposed carriers and HFE wildtypes. SNc R2* was lower in exposed H63D carriers than in unexposed carriers, whereas SNc FA was lower in exposed HFE wildtypes than in either unexposed HFE wildtypes or exposed H63D carriers. Serum iron and SNc FA measures correlated positively among exposed, but not unexposed, subjects. These data suggest that H63D heterozygosity is associated with lower neurotoxicity presumptively linked to paraquat. Future studies with larger cohorts are warranted to replicate these findings and examine potential underlying mechanisms, especially given the high prevalence of the H63D allele in humans. [ABSTRACT FROM AUTHOR]

Background Glioblastoma (GBM) is the most common and most malignant glioma. Nonglioblastoma (non-GBM) gliomas (WHO Grades II and III) are invasive and also often fatal. The goal of this study is to determine whether sex differences exist in glioma survival. Methods Data were obtained from the National Cancer Database (NCDB) for years 2010 to 2014. GBM (WHO Grade IV; N = 2073) and non-GBM (WHO Grades II and III; N = 2963) were defined using the histology grouping of the Central Brain Tumor Registry of the United States. Non-GBM was divided into oligodendrogliomas/mixed gliomas and astrocytomas. Sex differences in survival were analyzed using Kaplan–Meier and multivariable Cox proportional hazards models adjusted for known prognostic variables. Results There was a female survival advantage in patients with GBM both in the unadjusted (P =.048) and adjusted (P =.003) models. Unadjusted, median survival was 20.1 months (95% CI: 18.7-21.3 months) for women and 17.8 months (95% CI: 16.9-18.7 months) for men. Adjusted, median survival was 20.4 months (95% CI: 18.9-21.6 months) for women and 17.5 months (95% CI: 16.7-18.3 months) for men. When stratifying by age group (18-55 vs 56+ years at diagnosis), this female survival advantage appeared only in the older group, adjusting for covariates (P =.017). Women (44.1%) had a higher proportion of methylated MGMT (O6-methylguanine-DNA methyltransferase) than men (38.4%). No sex differences were found for non-GBM. Conclusions Using the NCDB data, there was a statistically significant female survival advantage in GBM, but not in non-GBM. [ABSTRACT FROM AUTHOR]

Welding has been associated with neurobehavioral disorders. Welding fumes contain severalmetals including copper (Cu), manganese (Mn), and iron (Fe) thatmay interact to influence welding-related neurotoxicity. Although welding-related airborne Fe levels are about 10-fold higher than Mn, previous studies have focused on Mn and its accumulation in the basal ganglia. This study examined differences in the apparent transverse relaxation rates [R2* (1/T2*), estimate of Fe accumulation] in the basal ganglia (caudate nucleus, putamen, and globus pallidus) between welders and controls, and the dose-response relationship between estimated Fe exposure and R2* values. Occupational questionnaires estimated recent and lifetime Fe exposure, and blood Fe levels and brainmagnetic resonance imaging (MRI) were obtained. Complete exposure and MRI R2* and R1 (1/T1:measure to estimate Mn accumulation) data from42 subjects with welding exposure and 29 controls were analyzed. We lders had significantly greater exposuremetrics and higher whole-blood Fe levels compared with controls. R2* in the caudate nucleus was significantly higher in welders after controlling for age, bodymass index, respirator use, caudate R1, and bloodmetals of Cu and Mn, whereas there was no difference in R1 values in the basal ganglia between groups. The R2* in the caudate nucleus was positively correlated with whole-blood Fe concentration. This study provides the first evidence of higher R2* in the caudate nucleus of welders, which is suggestive of increased Fe accumulation in this area. Further studies are needed to replicate the findings and determine the neurobehavioral relevance. [ABSTRACT FROM AUTHOR]

Restless legs syndrome is a neurological disorder characterized by an urgency to move the legs during periods of rest. Data from a variety of sources provide a compelling argument that the amount of iron in the brain is lower in individuals with restless legs syndrome compared with neurologically normal individuals. Moreover, a significant percentage of patients with restless legs syndrome are responsive to intravenous iron therapy. The mechanism underlying the decreased iron concentrations in restless legs syndrome brains is unknown. We hypothesize that the source of the brain iron deficit is at the blood–brain interface. Thus we analysed the expression of iron management proteins in the epithelial cells of the choroid plexus and the brain microvasculature in post-mortem tissues. The choroid plexus, obtained at autopsy, from 18 neurologically normal controls and 14 individuals who had primary restless legs syndrome was subjected to histochemical staining for iron and immunostaining for iron management proteins. Iron and heavy chain ferritin staining was reduced in the epithelial cells of choroid plexus in restless legs syndrome. Divalent metal transporter, ferroportin, transferrin and its receptor were upregulated in the choroid plexus in restless legs syndrome. Microvessels were isolated from the motor cortex of 11 restless legs syndrome and 14 control brains obtained at autopsy and quantitative immunoblot analyses was performed. Expression of heavy chain ferritin, transferrin and its receptor in the microvessels from restless legs syndrome was significantly decreased compared with the controls but divalent metal protein 1, ferroportin, prohepcidin, mitochondrial ferritin and light-chain ferritin remained unchanged. The presence of an iron regulatory protein was demonstrated in the brain microvasculature and the activity of this protein is decreased in restless legs syndrome; a finding similar to our earlier report in neuromelanin cells from the substantia nigra of restless legs syndrome brains. This study reveals that there are alterations in the iron management protein profile in restless legs syndrome compared with controls at the site of blood–brain interface suggesting fundamental differences in brain iron acquisition in individuals with restless legs syndrome. Furthermore, the decrease in transferrin receptor expression in the microvasculature in the presence of relative brain iron deficiency reported in restless legs syndrome brains may underlie the problems associated with brain iron acquisition in restless legs syndrome. The consistent finding of loss of iron regulatory protein activity in restless legs syndrome brain tissue further implicates this protein as a factor in the underlying cause of the iron deficiency in the restless legs syndrome brain. The data herein provide evidence for regulation of iron uptake and storage within brain microvessels that challenge the existing paradigm that the blood–brain barrier is merely a transport system. [ABSTRACT FROM AUTHOR]

Restless leg syndrome (RLS) is a sensorimotor disorder. Clinical studies have implicated the dopaminergic system in RLS, while others have suggested that it is associated with insufficient levels of brain iron. To date, alterations in brain iron status have been demonstrated but, despite suggestions from the clinical literature, there have been no consistent findings documenting a dopaminergic abnormality in RLS brain tissue. In this study, the substantia nigra and putamen were obtained at autopsy from individuals with primary RLS and a neurologically normal control group. A quantitative profile of the dopaminergic system was obtained. Additional assays were performed on a catecholaminergic cell line and animal models of iron deficiency. RLS tissue, compared with controls, showed a significant decrease in D2R in the putamen that correlated with severity of the RLS. RLS also showed significant increases in tyrosine hydroxylase (TH) in the substantia nigra, compared with the controls, but not in the putamen. Both TH and phosphorylated (active) TH were significantly increased in both the substantia nigra and putamen. There were no significant differences in either the putamen or nigra for dopamine receptor 1, dopamine transporters or for VMAT. Significant increases in TH and phosphorylated TH were also seen in both the animal and cell models of iron insufficiency similar to that from the RLS autopsy data. For the first time, a clear indication of dopamine pathology in RLS is revealed in this autopsy study. The results suggest cellular regulation of dopamine production that closely matches the data from cellular and animal iron insufficiency models. The results are consistent with the hypothesis that a primary iron insufficiency produces a dopaminergic abnormality characterized as an overly activated dopaminergic system as part of the RLS pathology. [ABSTRACT FROM PUBLISHER]

Infants are at high risk for iron deficiency and iron- deficiency anemia. This review summarizes evidence of long-term effects of iron deficiency in infancy. Follow-up studies from preschool age to adolescence report poorer cognitive, motor, and social-emotional function, as well as persisting neurophysiologic differences. Research in animal models points to mechanisms for such long-lasting effects. Potential mechanisms relate to effects of iron deficiency during brain development on neurometabolism, myelination, and neurotransmitter function. [ABSTRACT FROM AUTHOR]

Background. The magnitude of infant antiretroviral (ARV) exposure from breast milk is unknown. Methods. We measured concentrations of nevirapine, lamivudine, and zidovudine in serum and whole breast milk from human immunodeficiency virus type 1 (HIV-1)-infected women in Botswana receiving ARV treatment and serum from their uninfected, breast-feeding infants. Results. Twenty mother-infant pairs were enrolled. Maternal serum concentrations of nevirapine were high (median, 9534 ng/mL at a median of 4 h after nevirapine ingestion). Median breast-milk concentrations of nevirapine, lamivudine, and zidovudine were 0.67, 3.34, and 3.21 times, respectively, those in maternal serum. The median infant serum concentration of nevirapine was 971 ng/mL, at least 40 times the 50% inhibitory concentration and similar to peak concentrations after a single 2-mg/kg dose of nevirapine. The median infant serum concentration of lamivudine was 28 ng/mL, and the median infant serum concentration of zidovudine was 123 ng/mL, but infants were also receiving zidovudine prophylaxis. Conclusions. HIV-1 inhibitory concentrations of nevirapine are achieved in breast-feeding infants of mothers receiving these ARVs, exposing infants to the potential for beneficial and adverse effects of nevirapine ingestion. Further study is needed to understand the impact of maternal ARV treatment on breast-feeding HIV-1 transmission, infant toxicity, and HIV-1 resistance mutations among infected infants. [ABSTRACT FROM AUTHOR]

The effect of liposome-encapsulated (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC; cidofovir) was evaluated as prophylaxis in a rabbit model of experimentally induced retinitis caused by preretinal inoculation of herpes simplex virus type 1 (HSV-1). Cidofovir (100 µg) in liposomes (0.1 mL) was injected intravitreally 10–120 days before retinal inoculation with HSV-1. Twenty-two of 26 eyes pretreated with liposome-encapsulated cidofovir 10–60 days before HSV-1 inoculation were protected from experimentally induced retinitis, and 2 of 5 eyes pretreated 120 days before inoculation were protected. Intravitreal levels of cidofovir were low (0.7 µ/mL) but detectable 120 days after injection. One 100-µg intravitreal injection of liposome-encapsulated cidofovir appears to have a remarkably potent and prolonged (up to 4 months) antiviral effect in this experimental model ofHSV-1 retinitis. Since HPMPC is even more potent against cytomegalovirus than HSV-1, liposome-encapsulated cidofovir may prove to be effective local therapy for AIDS patients with cytomegalovirus retinitis. [ABSTRACT FROM PUBLISHER]

This study evaluated intravitreous and plasma ganciclovir and foscarnet concentrations after intravenous administration in AIDS patients with cytomegalovirus (CMV) retinitis and retinal detachment. Undiluted vitreous samples were prospectively obtained from 60 eyes (52 patients) at the time of pars plana vitrectomy. Thirty-three plasma samples (from 27 patients in the initial group of 52) were obtained simultaneously during surgery on 33 eyes. High-pressure liquid chromatography showed the mean vitreous ganciclovir concentrations in patients on induction and maintenance therapy were, respectively, 4.74 ± 1.49 µM (n = 24) and 3.29 ± 1.84 µM (n = 30; P = .005). Simultaneous plasma ganciclovir concentrations were less than the vitreous concentrations in 78% of the patients. The mean intravitreous foscarnet concentrations in patients receiving induction dosages were 189 ± 177 µM (n = 5) versus 163 ± 167 µM (n = 4; P > .20) for those receiving maintenance therapy. The foscarnet vitreous plasma concentration ratio averaged 1.43. Current drugs and doses for CMV retinitis result in borderline or progressively subtherapeutic concentrations. [ABSTRACT FROM PUBLISHER]

A phase I/II study evaluated the pharmacokinetics, tolerability, and antiviral activity of oral ganciclovir in persons infected with human immunodeficiency virus (HIV). Oral bioavailability ranged from 2.6% to 7.3%. The mean maximum serum concentration achieved at 1000 mg every 8 h was 1.11 µg/mL, and mean trough level was 0.54 µg/mL. The time to maximum serum drug concentration was 1.0–2.9 h, with a serum half-life of 3.0–7.3 h, suggesting prolonged oral absorption. Serious adverse events were uncommon. Decreased cytomegalovirus (CMV) shedding was observed from all sites. The median days (by dosage) to retinitis progression assessed by retinal examination after initiation of oral ganciclovir were 62 (1000 mg every 8 h), 148 (500 mg every 3 h), 75 (750 mg every 3 h), 148 (1000 mg every 3 h), and 139 (2000 mg every 8 h). Thus, oral ganciclovir has pharmacokinetic, toxicity, and antiviral profiles that may prove beneficial for both maintenance therapy of CMV retinitis and prevention of CMV disease in HIV-infected persons. [ABSTRACT FROM PUBLISHER]

To determine whether therapeutic intravitreal concentrations of ganciclovirare achieved after intravenous administration, vitreous samples were obtained intraoperatively from 23 eyes of 22 AIDS patients with retinal detachments associated with cytomegalovirus (CMV) retinitis. The mean intravitreal ganciclovir concentration of all samples was 0.93 ± 0.39 µg/mL (3.6 ± 1.5 µM). This level is near the published trough serum concentrations obtained with every-12-h intravenous dosing and well below the peak. It is significantlybelow the concentration of ganciclovir required to achieve 50% of viral plaque formation for many human CMV strains. Only a small decrease in vitreous drug levelswas observed as a function of time after last dose. Intravenous administration of ganciclovir results in near-steady-state subtherapeutic intravitreal ganciclovir concentrations for many CMV isolates. This may explain the difficultyof long-term complete suppression of CMV retinitis. [ABSTRACT FROM PUBLISHER]

The inhibition of viremia and p24 core antigenemia in patients infected with human immunodeficiency virus (HIV) was evaluated in separate multicenter, double-blind, placebo-controlled trials of zidovudine and ribavirin. Of 29 patients (14 with AIDS and 15 with AIDS-related complex [ARC]) enrolled in the zidovudine study, 16 received 250 mg of zidovudine every 4 h and 13 received placebo. No difference in HIV isolation from peripheral blood was observed at 20 w in treated versus placebo groups (79% vs. 82%). In patients tolerating zidovudine, mean p24 antigen levels dropped to 8.2% ± 8.1% of their baseline values, whereas in placebo recipients mean p24 antigen levels declined to 61.3% ± 40.8% of their baseline values (P < .005). In the ribavirin study, patients with ARC treated with either 800 mg or 600 mg of ribavirin daily or with placebo showed no consistent reduction in p24 antigenemia or decrease in HIV isolation. These data indicate that decline in p24 antigenemia can be a useful virologic marker in evaluation of new antiretroviral drugs. [ABSTRACT FROM PUBLISHER]

A rapid screening test for resistance to acyclovir, mediated by a lack of thymidine kinase (TK) activity in herpes simplex virus (HSV), was developed by utilizing the uptake of (125I]iododeoxycytidine (IdC) by infected Vera cells. Cells infected with TK+ virus demonstrate uptake of IdC within 3 hr of infection. The assay can detect as few as 690 pfu of virus. Cells infected with TK virus have an uptake of IdC similar to that of uninfected cells, whereas cells infected with TK+ generally have an uptake >10 times that of uninfected cells if tested when obvious viral cytopathic effect is present. All 19 clinical HSV isolates tested were correctly identified as TK+. Of 17 blinded HSV isolates tested, all six TK- isolates were correctly identified. A single strain with an ID50 of 3.4 µg/ml and an altered TK substrate specificity was incorrectly classified as TK+. The assay is a useful, rapid screening test for viral TK activity. [ABSTRACT FROM PUBLISHER]

A standard challenge with percutaneous smallpox vaccine was administered to 629 children six to 12 months after percutaneous primary inoculation with one of four vaccines (New York City Board of Health strains grown in calf lymph or chorioallantoic membranes, the Lister vaccine, or the CV-I strain). Of those who had had major reactions on primary vaccination, 8%–21% responded to revaccination with a typical primary-type skin response. In contrast, such a primary-type response occurred in 50% of those who on primary vaccination had developed serum antibody in the absence of major reactions and in 83% of those who had had no serologic or clinical evidence of primary "take." Skin lesions on revaccination tended to be largest in those whose primary vaccination was with CV-I, although fever and minor complications were not more frequent. Moreover, even in children who had received CV-I vaccine, skin responses to challenge vaccine were clearly attenuated when compared with responses of children who had not had takes on primary vaccination. Sizes of lesions and acceleration of skin erythema after challenge were related in most children to titers of both hemagglutination-inhibiting and neutralizing antibody at the time of revaccination. One month after revaccination, neutralizing antibody was present in 93%–96% of those with takes on primary vaccination with New York City or Lister vaccines, but only 75% of CV-1 vaccinees. [ABSTRACT FROM PUBLISHER]

Six months after subcutaneous vaccination with one of four smallpox vaccines, 655 children were challenged with a standard percutaneous smallpox vaccine. Response to reimmunization was characterized by a significant acceleration and diminution of skin response, but not to the degree seen in an equivalent group who had received their primary immunization percutaneously. Fever after revaccination was absent if there had been a “take” with primary subcutaneous vaccination. The overall incidence of minor vaccine-related complications with revaccination was 2½%' The neutralizing antibody response to revaccination was markedly reduced, as compared to that of children who received either one or two successful percutaneous vaccinations. Subcutaneous vaccination followed by percutaneous vaccination is not recommended as a schedule for smallpox immunization, because complications are not avoided, and the incidence and mean titer of resultant neutralizing antibody are low. [ABSTRACT FROM PUBLISHER]

As part of a large study designed to develop schedules for smallpox immunization with reduced morbidity, 799 children received primary immunization with subcutaneous vaccine. Four vaccines (New York City Board of Health calf lymph, New York City chorioallantoic membrane, CV-1, and Lister) at three dosages (103, 104, 105 pockforming units) were administered. Eighty-two percent responded with hemagglutination- inhibiting antibody at one month, and only 22% with neutralizing antibody. There was no correlation between concentration of vaccine and antibody response. The CV-1 strain was slightly but significantly less likely to induce antibody than the other three vaccines. Subcutaneous vaccination was not associated with significant temperature elevation in general. However, some children developed erythema at the vaccination site or a swollen arm, and fever did tend to occur in this small group. Four children developed nonspecific vaccinia-related rashes, and one had generalized vaccinia. [ABSTRACT FROM PUBLISHER]

In an investigation of the antigenicity and reactogenicity of four smallpox vaccines, 786 children received primary percutaneous vaccination with vaccine in one of three concentrations, 106, 107, or 108 pock-forming units/ml. Dose-response curves indicated that the three licensed vaccines (New York City Board of Health strains grown in calf lymph or chorioallantoic membrane, and the Lister vaccine) had similar potencies, but the CV-l strain was about 10-fold less infectious. CV-l also produced smaller skin lesions than the other three vaccines, and the incidence of fever in CV-I vaccinees who developed either “major reactions” or serum antibody was not significantly different from that in children in all vaccine groups with no evidence of “take.” Hemagglutination-inhibiting antibody was consistently seen in individuals who received potent New York City and Lister vaccines, and neutralizing antibody was induced in 82%–85% of children in this group who had some evidence of take (production of hemagglutination-inhibiting antibody or major reaction). Only 30% of CV-l vaccinees with takes produced neutralizing antibody. Minor complications occurred in all groups, but most often in children who received the New York City strains. [ABSTRACT FROM PUBLISHER]

Ceftriaxone, a cephalosporin with an extended half-life and excellent antibacterial activity was used to treat bacterial meningitis, given as a single daily intravenous dose of 100 mg/kg on day one, followed by 80 mg/kg daily. A total of 22 patients were treated, of whom 14 had Haemophilus influenzae type b, five had Streptococcus pneumoniae and three Neisseria meningitidis isolated from their CSF. The CSF of all patients became sterile within 24-48 h. The CSF ceftriaxone concentrations 24 h after dosing were 10 to 100-fold higher than the MIC of the pathogenic bacteria early in therapy, and five to 50-fold higher at the end of therapy. Side effects encountered included mild diarrhoea (32%), thrombocytosis (77%) and neutropenia (9%), but none caused therapy to be stopped. Ceftriaxone is a safe and effective antibiotic for the treatment of bacterial meningitis when administered once daily. [ABSTRACT FROM AUTHOR]

Since the 1950s the U.S. military has used intramuscular injections of benzathine penicillin G (BPG) to control outbreaks of respiratory disease. In an effort to find an alternative prophylaxis, a randomized field trial was conducted among 1,016 male U.S. Marine trainee volunteers at high risk for respiratory disease. Participants were evaluated for evidence of acute respiratory infection by serological tests on pretraining and posttraining sera (63 days apart). Oral azithromycin prophylaxis (500 mg/w) outperformed BPG, preventing infection from Streptococcus pyogenes (Efficacy [E] = 84%; 95% confidence interval [CI], 63%–93%), Streptococcus pneumoniae (E = 80%; 95% CI, 50%– 92%), Mycoplasma pneumoniae (E = 64%; 95% CI, 25%–83%), and Chlamydia pneumoniae (E = 58%; 95% CI, 15%–79%) in comparison with results in a no-treatment group. Azithromycin group subjects reported few side effects and less respiratory symptoms than the BPG and no-treatment groups. According to serological tests, oral azithromycin is an effective alternative prophylaxis to BPG for military populations. [ABSTRACT FROM PUBLISHER]

Bactericidal antibodies were detected in sera of all 24 persons with bacteriologically confirmed pertussis, 15 of whom had not been immunized. In 10 of the 15 un-immunized persons, increases in concentration of bactericidins were associated with the infection. The development of bactericidal antibody during pertussis may indicate a role in immunity although a mechanism has not been demonstrated. [ABSTRACT FROM PUBLISHER]