Evaluation of ocular and systemic endpoints after radiation of posterior uveal melanoma - A systematic review and meta-analysis.

Background: Due to the large number of radiotherapeutic options for treatment of posterior uveal melanoma (UM), advantages of each option regarding important clinical endpoints have yet to be determined. Therefore, objective of this systematic review was to analyze the numerous pro- and retrospective cohort studies focusing on the efficacy of different radiotherapeutic options for UM in adults, considering local tumor control, overall survival, visual acuity, eye preservation, metastasis, radiation side effects and dose rates. Methods: The Review was performed based on the Cochrane Handbook of Systematic Reviews. The PubMed database was searched for studies published from January 1st, 2000, up to December 31st, 2021. Research, study selection and critical appraisal was performed by two reviewers. The risk of bias assessment was performed through the revised Cochrane risk of bias tools RoB 2 and ROBINS-I. A meta-analysis of proportions was performed using R (R version 4.1.3, library: meta, procedure: metaprop). This systematic review was registered with Prospero (ID CRD42022311758). Results: Of 4886 studies identified in the database, a total of 20 studies with 4979 participants were included in the qualitative synthesis. Through critical appraisal with ROBINS-I and RoB 2, studies received a 'moderate', 'serious' or 'some concerns' overall risk of bias. Heterogeneity analysis allowed for meta-analysis of proportion of 3 outcome-therapy combinations: local tumor control with I-125 Brachytherapy (proportion: 0.94, CI 95 %: 0.91-0.98), local tumor control with proton therapy (proportion: 0.96, CI 95 %: 0.92-1.00) and eye preservation with I-125 brachytherapy (proportion: 0.91, CI 95 %: 0.88-0.93). This shows local tumor control to be at 94 % with I-125 brachytherapy and at 96 % with proton therapy, as well as an eye preservation rate of 91 % with I-125 brachytherapy. Discussion: The evaluation of outcomes of radiotherapy in UM is limited because of missing data on radiation doses as well as great heterogeneity of study protocols. Radiation therapy outcomes are so far not comparable. Therefore, we recommend for upcoming studies on this topic to provide the biological effective dose (BED) or the equivalent dose in 2 Gy fractions (EQD2) per eye structure, thereby enabling a comparison of outcomes of different forms of radiation therapy.

Iron deficiency decreases dopamine D1 and D2 receptors in rat brain.

Iron deficiency (ID) in early life is known to alter neurological development and functioning, but data regarding specific effects on dopamine biology are lacking. The objective of this study was to determine the extent of functional alterations in dopamine receptors in two dopaminergic tracts in young, growing, iron-deficient rats. Forty male and 40 female weanling Sprague-Dawley rats were fed either an iron-deficient (ID) diet or control (CN) diet for 6 weeks. ID decreased densities of D(1) and D(2) receptors in the caudate-putamen and decreased D(2) receptor densities in the nucleus accumbens. There were no apparent effects of ID on the affinities for the ligands in either receptor in several brain regions. In situ hybridization studies for both dopamine receptors revealed no significant effect of ID on mRNA expression for either receptor. Iron-deficient rats had a significantly higher ED(50) for raclopride-induced hypolocomotion in male and female rats compared to control rats of each sex. The loss of iron in the striatum due to dietary ID was significantly correlated with the decrease in D(2) receptor density; however, this relationship was not apparent in other brain regions. These experiments thus demonstrate abnormal dopamine receptor density and functioning in several brain regions that are related to brain regional iron loss. Importantly, the impact of ID on dopamine was more pronounced in males than females, demonstrating sex-related different sensitivities to nutrient deprivation.

Iron deficiency alters dopamine transporter functioning in rat striatum.

Iron deficiency anemia in early life produces profound changes in both in vivo and in vitro evaluations of dopamine (DA) functioning. This study employed both behavioral and biochemical approaches to examine the biological bases of alterations in striatal DA metabolism seen in iron-deficient rats. The purpose was to determine whether the DA transporter (DAT) was functionally altered in postweaning iron deficiency. Male and female 21-d-old Sprague-Dawley rats (n = 40) were fed either an iron-deficient (ID) diet (3 mg Fe/kg diet) or a control (CN) diet (35 mg Fe/kg diet) for 4 wk before behavioral testing. Motor activity responses to graded doses (3.75-30 mg/kg body) of the DA uptake inhibitor, cocaine, were significantly blunted in iron-deficient rats with a 50% higher half-maximal effective dose (ED(50)) in both males and females (CN-female, 7.1 +/- 0.9 mg/kg; ID-female, 11.2 +/-1.3 mg/kg; CN-male, 12.0 +/- 0.7 mg/kg; and ID-male, 17.0 +/- 1.8 mg/kg). Radioligand binding assays with (3)H-1-(2-(diphenylmethoxy)-ethyl)-4-(3-phenylpropyl) piperazine ((3)H-GBR12935) demonstrated that iron deficiency did not alter the affinity of the ligand for the DAT but did significantly decrease the density of the transporter by 30% in caudate putamen and 20% in nucleus accumbens. Iron deficiency also significantly decreased (3)H-DA uptake into striatal synaptosomes, but did not affect release of DA with potassium chloride stimulation. These experiments provide supporting evidence that elevated levels of extracellular DA in the striatum of iron-deficient rats is likely to be the result of decreased DAT functioning and not increased rates of release.

Iron deficiency in young rats alters the distribution of vitamin A between plasma and liver and between hepatic retinol and retinyl esters.

We assessed whether iron deficiency alters the concentration of vitamin A (VA) in plasma or liver and the chemical distribution between hepatic unesterified and esterified retinol. Weanling male Sprague-Dawley rats (n = 10/group) were allocated to one of four diet groups: low iron (ID3, 3 mg of elemental iron/kg diet), marginal iron (ID15, 15 mg/kg), control diet food-restricted to the ID3 group (FR, 35 mg/kg), and control diet ad libitum consumption (AD, 35 mg/kg). Both ID3 and FR rats grew less than AD and ID15 rats. At the end of 5.5 wk, plasma retinol concentrations of the ID3 and FR rats were reduced >40% compared to ID15 and AD rats [Kruskal-Wallis test (K-W), P < 0.0042)]. Paradoxically, the hepatic VA concentration was greater in FR rats, with accumulation of more retinyl esters and retinol compared to the other dietary groups. Concentrations of hepatic retinyl esters and retinol did not differ among the other groups, but the molar ratio of hepatic retinyl esters to retinol was greater in ID3 rats (20.1 +/- 1.4) compared to ID15 rats (13.8 +/- 1.6, P = 0.02), AD (11.3 +/- 2.1, P < 0.0042) and FR (9.5 +/- 1.1, P < 0.0042). Iron deficiency may cause changes in liver and plasma VA that are refractory to VA intake, and thus a benefit may be derived from combining iron and VA supplements during nutrition interventions.

Regional brain iron, ferritin and transferrin concentrations during iron deficiency and iron repletion in developing rats.

Iron deficiency in young rats leads to a decrease in brain iron and ferritin concentrations, an increase in transferrin (Tf) concentration, and an increased rate of uptake of iron from the plasma pool. We conducted two experiments to determine whether brain iron, Tf and ferritin respond quickly to iron repletion and to determine whether brain regions respond heterogeneously. Weanling male Sprague-Dawley rats were fed an iron-deficient diet (<5 mg/kg Fe) for 2 wk followed by an iron-adequate diet (REPL group, 35 mg/kg Fe in Experiment 1 and 15 mg/kg Fe in Experiment 2) for 2 or 4 wks, respectively. Age-matched iron-deficient (ID) and control rats composed the other two groups. Fourteen days of repletion with 35 mg/kg Fe dietary treatment were adequate to normalize hematology, brain microsomal and cytosolic Fe and brain ferritin (Experiment 1). Brain transferrin concentrations in REPL rats, however, were significantly above the levels of controls. Regional brain iron decreased heterogeneously due to dietary iron deficiency (Experiment 2), with some regions having a propensity to keep iron (e.g., substantia nigra, pons, and thalamus) and others losing significant amounts of iron (cortex and hippocampus). Ferritin and Tf concentrations also varied significantly across brain regions in ID and control rats. The hippocampus had the most dramatic Tf response to iron deficiency with elevations of approximately 100%, whereas other regions, except striatum, were unaffected. The brain of developing rats thus distributes iron and iron regulatory proteins differently from the brain of adult rats and is quite avid in its reacquisition of iron during iron therapy.

In vivo dopamine metabolism is altered in iron-deficient anemic rats.

Previous studies of dopamine metabolism in iron-deficient rats demonstrated an elevation in extraneuronal levels of dopamine and a depression in the number of dopamine D2 receptors; however, the importance of anemia per se and the reversibility of these observations are not completely resolved. The purpose of this study was to determine if in vivo reuptake of caudate dopamine is altered by iron deficiency anemia, if it is reversible with iron therapy, and if anemia per se produced the same effects on dopamine metabolism. Male Sprague-Dawley rats (21-d old) were fed an iron-deficient diet (4 mg Fe/kg diet) and then iron repleted (5 mg iron dextran), or were fed an iron adequate diet (35 mg Fe/kg diet) and then given phenylhydrazine to induce hemolytic anemia. In vivo microdialysis was performed in steady-state conditions both before and after iron or no therapy and was followed by an intraperitoneal injection of a dopamine reuptake blocker (cocaine-HCl 30 mg/kg). Thirty percent higher extracellular dopamine levels in the caudate-putamen were observed in iron-deficient rats compared with control rats, but no differences were observed in tissue levels. Hemolytic anemic and iron-repleted rats had normal extracellular dopamine levels. The response to dopamine reuptake blockade was significantly attenuated in iron-deficient rats compared with control, iron-repleted, or hemolytic anemic rats. These experiments provide evidence that iron deficiency blunts the dopamine reuptake mechanism, that this is a reversible process in postweaning rats, and that anemia per se does not cause the increased extracellular dopamine levels.

Socioeconomic studies of high-level nuclear waste disposal.

The socioeconomic investigations of possible impacts of the proposed repository for high-level nuclear waste at Yucca Mountain, Nevada, have been unprecedented in several respects. They bear on the public decision that sooner or later will be made as to where and how to dispose permanently of the waste presently at military weapons installations and that continues to accumulate at nuclear power stations. No final decision has yet been made. There is no clear precedent from other countries. The organization of state and federal studies is unique. The state studies involve more disciplines than any previous efforts. They have been carried out in parallel to federal studies and have pioneered in defining some problems and appropriate research methods. A recent annotated bibliography provides interested scientists with a compact guide to the 178 published reports, as well as to relevant journal articles and related documents.

Disaster at Buffalo Creek. Loss of communality at Buffalo Creek.

The survivors of the Buffalo Creek disaster suffered both individual and collective trauma, the latter being reflected in their loss of communality. Human relationships in this community had been derived from traditional bonds of kinship and neighborliness. When forced to give up these long-standing ties with familiar places and people, the survivors experienced demoralization, disorientation, and loss of connection. Stripped of the support they had received from their community, they became apathetic and seemed to have forgotten how to care for one another. This was apparently a community that was stronger than the sum of its parts, and these parts--the survivors of the Buffalo Creek flood--are now having great difficulty finding the personal resources to replace the energy and direction they had once found in their community.