Radiation dose rates of differentiated thyroid cancer patients after <Superscript>131</Superscript>I therapy

Postoperative ¹³¹I treatment for differentiated thyroid cancer (DTC) can create a radiation hazard for nearby persons. The present prospective study aimed to investigate radiation dose rates in ¹³¹I-treated DTC patients to provide references for radiation protection. A total of 141 ¹³¹I-treated DTC patients were enrolled, and grouped into a singular treatment (ST) group and a repeated treatment (RT) group. The radiation dose rate of ¹³¹I-treated patients was measured. The rate of achieving discharge compliance and restricted contact time were analyzed based on Chinese regulations. Multivariate logistic regression analysis was used to analyze the independent factors associated with the clearance of radioiodine. The rate of achieving discharge compliance (¹³¹I retention <?400 MBq) was 79.8 and 93.7% at day 2 (D2) for the ST and RT groups, respectively, and reached 100% at D7 and D4, respectively. The restricted contact time with ¹³¹I-treated patients at 0.5 m for medical staff, caregivers, family members, and the general public ranged from 4 to 7 days. Multivariate logistic regression analysis showed that the 24-h iodine uptake rate was the only significant factor associated with radioiodine clearance. For the radiation safety of ¹³¹I-treated DTC patients, the present results can provide radiometric data for radiation protection.     

Effect of Recombinant Human Thyrotropin on the Uptake of Radioactive Iodine (123I) in Dogs with Thyroid Tumors

In humans, recombinant human thyrotropin (rhTSH) enhances radioactive iodine uptake (RAIU) in patients with differentiated thyroid cancer. No studies have been performed in veterinary medicine to optimize radioiodine treatment of thyroid cancer. The aim of this study was to evaluate the effect of rhTSH on the uptake of radioiodine-123 (¹²³I) in dogs with thyroid tumors. Nine dogs with thyroid neoplasia were included in this prospective cross-over study. The dogs were divided in 2 groups. In one group, ¹²³I was administered for a baseline RAIU determination in week 1. In week 2 (after a washout period of 2 weeks), these dogs received rhTSH (100 μg IV) 24 h before ¹²³I injection. In the other group the order of the protocol was reversed. For each scan, the dogs received 37 MBq (1 mCi) of ¹²³I intravenously (IV) and planar scintigraphy was performed after 8 and 24 h for tumor RAIU calculation. Overall, rhTSH administration caused no statistically significant change on thyroid tumor RAIU at 8 h (p = 0.89) or at 24 h (p = 0.98). A significant positive correlation was found between the effect of rhTSH on tumor 8h-RAIU and rhTSH serum concentrations at 6 h (τ = 0.68; p = 0.03), at 12 h (τ = 0.68; p = 0.03) and at 24 h (τ = 0.78; p = 0.02) after rhTSH injection. This study suggests that IV administration of 100 μg rhTSH 24 h before ¹²³I has an inconsistent effect on thyroid tumor RAIU. Further studies are necessary to determine the best protocol of rhTSH administration to optimize thyroid tumor RAIU.     

Seventeen-year follow-up study on chromosomal aberrations in five victims accidentally exposed to several Gy of <Superscript>60</Superscript>Co γ-rays

On 25 June 1990, a radiation accident occurred in a ⁶⁰Co source radiation unit in Shanghai, due to violations in operation regulations. This accident resulted in the exposure of seven individuals to acute high-dose and dose-rate whole-body external irradiation. Conventional chromosomal aberration analysis, G-banding automatic karyotype analysis and/or fluorescent in situ hybridization (FISH) painting methods were used to analyze chromosomal aberrations in peripheral blood lymphocytes from five of the victims 24 h to 17 years after accidental exposure to 1.9–5.1 Gy of ⁶⁰Co γ-rays. The frequency of unstable chromosomal aberrations (dicentrics and rings) remained at constant levels 1 month after exposure. Three months after exposure, the frequency was reduced by 20–40% in three victims, while no reduction was seen in the other two victims. Twelve years after exposure, the number of dicentrics and rings decreased by more than 90%, and did not reveal a dose-dependent relationship. However, even at 12–17 years after exposure, stable chromosome aberrations, dominated by translocations, remained at a high level in a dose-dependent manner. The frequency of stable chromosomal aberrations detected by FISH showed a similar dose-dependent relationship as that detected by karyotype analysis of G-banding chromosomes. The G-banding analysis also suggested that the pattern of chromosome breakpoints is random. The FISH data showed a decreasing tendency with time for chromosome translocation frequency in the peripheral lymphocytes, and the rate of reduction varied among different individuals. It is likely that the higher dose the victim received, the lesser the translocation frequency decreased with time. The G-banding data also showed that the rate of reduction of translocations is different among individuals. From 5 to 17 years after accidental irradiation, a very small reduction (~10%) of translocation frequency was observed in victims C and D, while there was about a 35% reduction (the highest among the victims) for victim G who received the smallest dose (1.9 Gy). These observations can be used to validate the existence of chromosomal aberrations in peripheral blood lymphocytes as a biological dosimeter for radiation exposures.     

Micronucleus formation in lymphocytes of children from the vicinity of Chernobyl after <Superscript>131</Superscript>I therapy

After the Chernobyl accident a statistically significant increase in the number of children with thyroid tumours was observed. In this study 166 children with and 75 without thyroid tumours were analysed for micronucleus formation in peripheral blood lymphocytes using the cytochalasin B approach. The following factors did not significantly affect micronucleus formation: gender, age at the time of the first ¹³¹I treatment, tumour stage, tumour type, or metastases; a statistically significant increase in the number of micronuclei, however, was observed for the residents of Gomel compared to other locations, such as Brest, Grodno, and Minsk. The children with tumours received ¹³¹I treatment after surgical resection of the tumours. This gave us the opportunity to systematically follow the effect of ¹³¹I on micronucleus formation. A marked increase was observed 5 days after the ¹³¹I treatment followed by a decrease within a 4–7 months interval up to the next application, but the pre-treatment levels were not achieved. Up to 10 therapy cycles were followed each including an analysis of micronucleus formation before and 5 days after ¹³¹I application. The response of the children was characterised by clear individual differences and the increase/decrease pattern of micronucleus frequencies induced by iodine-131 was correlated with a decrease/increase pattern in the number of lymphocytes.     

Mutagenicity of diagnostic and therapeutical doses of radiopharmaceutical iodine-131 in Wistar rats

Iodine-131 (¹³¹I) is a radioisotope used for the diagnosis and treatment of thyroidal disorders such as hyperthyroidism and cancer. During its decay, ¹³¹I emits beta particles and gamma rays; its physical half-life is 8 days, and it is accumulated preferentially in the thyroid tissue. This study aimed to evaluate the cytotoxicity and mutagenicity of diagnostic and therapeutic doses of ¹³¹I using bone marrow cells of rats treated in vivo in a test system with a single dose by gavage. Concentrations of 5, 25, 50 and 250 μCi in 1 ml of water were used, and after 24 h, the animals were killed. Also, a concentration of 25 μCi/ml of water was used, and the animals were killed after 5 days. The results showed that no concentration of ¹³¹I was cytotoxic and that all concentrations were mutagenic. As a result, there was no statistically significant difference detected by the χ² test in the induction of chromosomal aberrations between the different doses. Thus, the present study demonstrated a significant increase in chromosomal aberration in bone marrow cells exposed to ¹³¹I regardless of the dose or the treatment time.     

Cytogenetic biodosimetry and dose-rate effect after radioiodine therapy for thyroid cancer

This study set out to investigate chromosomal damage in peripheral blood lymphocytes of thyroid cancer patients receiving ¹³¹I for thyroid remnant ablation or treatment of metastatic disease. The observed chromosomal damage was further converted to the estimates of whole-body dose to project the adverse side effects. Chromosomal aberration analysis was performed in 24 patients treated for the first time or after multiple courses. Blood samples were collected before treatment and 3 or 4 days after administration of 2–4 GBq of ¹³¹I. Both conventional cytogenetic and chromosome 2, 4 and 12 painting assays were used. To account for dose-rate effect, a dose-protraction factor was applied to calculate the whole-body dose. The mean dose was 0.62 Gy (95% CI: 0.44–0.77 Gy) in the subgroup of patients treated one time and 0.67 Gy (95% CI: 0.03–1.00 Gy) in re-treated patients. These dose estimates are about 1.7-fold higher than those disregarding the effect of exposure duration. In re-treated patients, the neglected dose-rate effect can result in underestimation of the cumulative whole-body dose by the factor ranging from 2.6 to 6.8. Elevated frequency of chromosomal aberrations observed in re-treated patients before radioiodine therapy allows estimation of a cumulative dose received from all previous treatments.     

Clozapine Administration Modifies Neurotensin Effect on Synaptosomal Membrane Na<Superscript>+</Superscript>, K<Superscript>+</Superscript> -ATPase Activity

Na⁺, K⁺-ATPase is inhibited by neurotensin, an effect which involves the peptide high affinity receptor (NTS1). Neurotensin effect on cerebral cortex synaptosomal membrane Na⁺, K⁺-ATPase activity of rats injected i.p. with antipsychotic clozapine was studied. Whereas 3.5 × 10⁻⁶ M neurotensin decreased 44% Na⁺, K⁺-ATPase activity in the controls, the peptide failed to modify enzyme activity 30 min after a single 3.0, 10.0 and 30.0 mg/kg clozapine dose. Neurotensin decreased Na⁺, K⁺-ATPase activity 40 or 20% 18 h after 3.0 or 5.6 mg/kg clozapine administration, respectively, and lacked inhibitory effect 18 h after 17.8 and 30.0 mg/kg clozapine doses. Results indicated that the clozapine treatment differentially modifies the further effect of neurotensin on synaptosomal membrane Na⁺, K⁺-ATPase activity according to time and dose conditions employed. Taken into account that clozapine blocks the dopaminergic D2 receptor, findings obtained favor the view of an interplay among neurotensinergic receptor, dopaminergic D2 receptor and Na⁺, K⁺-ATPase at synaptic membranes.     

Effects of Ketamine on the Balance of Ions Ca<Superscript>2+</Superscript>, Mg<Superscript>2+</Superscript>, Cu<Superscript>2+</Superscript> and Zn<Superscript>2+</Superscript> in the Ischemia-reperfusion Affected Spinal Cord Tissues in Rabbits

To test the effects of ketamine on metal ion balance in the spinal cord tissues after ischemic reperfusion (I/R), 24 white adult Japanese rabbits were randomly assigned to sham operation group, I/R group or ketamine-treated I/R group. Spinal cord injuries in I/R group and ketamine-treated I/R group were induced by aortic occlusions. Rabbits in ketamine-treated I/R group were intravenously infused 10 mg/kg ketamine twice: once at 10 min before aortic clamping and once at the onset of reperfusion. Post-operative neurological functions and concentrations of ions Ca²⁺, Mg²⁺, Cu²⁺ and Zn²⁺ in the spinal cord were assessed. Compared with the sham operation group, rabbits in the I/R group showed significantly worsened neurological functions as scored with the modified Tarlov criteria and altered concentrations of ions Ca²⁺, Mg²⁺, Cu²⁺ and Zn²⁺. These unfavorable changes were significantly reversed in the ketamine-treated I/R group, suggesting that the potent protective effects of ketamine against the I/R-induced spinal cord injuries may be due to its ability to maintain ion balance in the I/R affected tissues.     

Role of caffeic acid phenethyl ester on mitomycin C induced clastogenesis: analysis of chromosome aberrations,micronucleus, mitotic index and adenosine deaminase activity <Emphasis Type="Italic">in vivo</Emphasis>

The aim of the present investigation is to determine whether the caffeic acid phenethyl ester (CAPE) in combination with mitomycine-C (MMC) can ameliorate MMC-induced clastogenesis in the bone marrow cells of mice. The scoring of chromosomal aberrations, mitotic activity and micronuclei were undertaken in the current study as markers of clastogenicity. The action of CAPE in adenosine deaminase enzyme (ADA) activities of serum, thymus and spleen were also investigated. The animals were orally administered CAPE alone at the doses 5 or 10 mg kg b.wt.^-1 for 5 days then sacrificed 24 hours after the CAPE administration. MMC was administered to mice either alone at a single dose (2 mg kg b.wt.^-1) by intraperitoneal injection, before or after CAPE treatment. Pre or post – treatment with two doses of CAPE significantly decreased the number of chromosomal aberrations, micronuclei and adapted the mitotic activity reduction in the bone marrow cells of mice induced by MMC when compared with only MMC given group. In addition, combination treatment with MMC caused a significant decrease in the activities of ADA in serum, thymus and spleen. The results of this study showed that ADA activity probably related to high levels of reactive oxygen species. This study concluded that the protective effect of CAPE against MMC clastogenesis resides at least in part, in its antioxidant effects.     

Changes in Na<Superscript>+</Superscript>, K<Superscript>+</Superscript>-ATPase Activity and Alpha 3 Subunit Expression in CNS After Administration of Na<Superscript>+</Superscript>, K<Superscript>+</Superscript>-ATPase Inhibitors

The expression of Na⁺, K⁺-ATPase α3 subunit and synaptosomal membrane Na⁺, K⁺-ATPase activity were analyzed after administration of ouabain and endobain E, respectively commercial and endogenous Na⁺, K⁺-ATPase inhibitors. Wistar rats received intracerebroventricularly ouabain or endobain E dissolved in saline solution or Tris–HCl, respectively or the vehicles (controls). Two days later, animals were decapitated, cerebral cortex and hippocampus removed and crude and synaptosomal membrane fractions were isolated. Western blot analysis showed that Na⁺, K⁺-ATPase α3 subunit expression increased roughly 40% after administration of 10 or 100 nmoles ouabain in cerebral cortex but remained unaltered in hippocampus. After administration of 10 μl endobain E (1 μl = 28 mg tissue) Na⁺, K⁺-ATPase α3 subunit enhanced 130% in cerebral cortex and 103% in hippocampus. The activity of Na⁺, K⁺-ATPase in cortical synaptosomal membranes diminished or increased after administration of ouabain or endobain E, respectively. It is concluded that Na⁺, K⁺-ATPase inhibitors modify differentially the expression of Na⁺, K⁺-ATPase α3 subunit and enzyme activity, most likely involving compensatory mechanisms.     

The genotoxic and anti-genotoxic effects of <Emphasis Type="Italic">Stachys petrokosmos</Emphasis> leaf extract in human lymphocytes using microsomal fractions

The genotoxic and anti-genotoxic effects of Stachys petrokosmos leaf extracts (Sp) were investigated in human lymphocytes. The cells were treated with 1.5, 3.0 and 6.0 μL/mL concentrations of Sp leaf extracts for 24 and 48 h treatment periods in the absence and presence of metabolic activator (S9mix). In the absence of S9mix, Sp alone did not induce chromosome aberrations and formation of micronucleus while inducing the mean sister chromatid exchange at the highest concentration. In addition, Sp decreased the mutagenic effect of mitomycin-c. Sp alone showed a cytotoxic effect determined by a decrease in the proliferation index, mitotic index and nuclear division index. On the other hand a mixture of Sp and mitomycin-c resulted in a higher cytotoxic effect especially for 48 h treatment period. In the presence of S9mix, Sp was not genotoxic and cytotoxic however, it showed an anti-genotoxic effect by decreasing the effects of cyclophosphamide.     

Evaluation Of Various Doses Of Recombinant Human Thyrotropin In Patients With Multinodular Goiters

ObjectiveTo assess the safety, adverse effects, and radioactive iodine uptake (RAIU) of recombinant human thyrotropin (rhTSH) using a range of doses in patients with multinodular goiters.MethodsIn this open-label study conducted between June 2002 and December 2004, euthyroid patients with small nontoxic multinodular goiters and normal thyrotropin concentrations were recruited from 4 sites in the United States. Baseline assessments included thyroid function tests, electrocardiogram, Holter monitoring, hyperthyroid symptom scale, flow-volume loop, and measurement of thyroglobulin and thyroperoxidase antibodies. Patients had a baseline 24-hour scan and thyroid iodine I 123 (¹²³I) uptake evaluated at 6, 24, and 48 hours after rhTSH administration. Each patient received a single intramuscular injection of 0.03-mg, 0.1-mg, or 0.3-mg rhTSH followed 24 hours later by 400 μCi ¹²³I orally. Iodine 123 uptakes were again measured 6, 24, and 48 hours later, and a scintigram scan was performed at 24 hours. Thyroid function tests, flow-volume loop, Holter monitoring and/or electrocardiograms, and thyroid ultrasonography to assess thyroid size were performed serially.ResultsTwenty-eight patients participated. Median goiter size was 20 mL (range, 7-79 mL). After each rhTSH dose, the radioiodine uptake approximately doubled at each time point compared with baseline uptake. Small rises in serum thyroxine and triiodothyronine were seen in some patients, especially after 0.3-mg rhTSH, and mild symptoms of hyperthyroidism developed in several patients. Flow-volume loop showed transient, mild asymptomatic worsening in 1 patient with a 35.2 mL goiter, although thyroid volume measurements were unchanged. Minor electrocardiogram and/or Holter changes were seen in several patients.ConclusionsA flat dose-response curve exists over the range of rhTSH doses tested, with an approximate doubling of thyroid RAIU. All patients tolerated rhTSH well, but the rise in thyroid hormone levels and adverse effects after rhTSH doses of 0.1 mg or higher theoretically might not be well tolerated in older or sicker patients and appear unjustified given the lack of a greater rise in RAIU compared with the 0.03-mg dose. Future studies evaluating rhTSH doses less than 0.1 mg in patients with multinodular goiter are justified. (Endocr Pract. 2008;14:832-839)     

Molecular cytogenetic characterization of a new wheat <Emphasis Type="Italic">Secale africanum</Emphasis> 2R<Superscript>a</Superscript>(2D) substitution line for resistance to stripe rust

A stable, highly fertile wheat Secale africanum substitution line LF24, derived from the F₇ generation of a cross between Mianyang11 (MY11) and Triticum durum, S. africanum amphiploid (YF) was identified through molecular cytogenetic analysis. Application of C-banding, in situ hybridization and molecular markers analysis showed that LF24 was a wheat S. africanum 2R^a(2D) substitution line. When inoculated with stripe rust isolates, T. durum and MY11 were highly susceptible, while S. africanum, YF and LF24 were immune. It is confirmed through molecular cytogenetic analysis that the stripe rust resistance of LF24 was derived from S. africanum chromosome 2R^a. We compared the banding patterns and disease resistance of reported chromosomes 2R from different S. cereale introduced into wheat background, and found that there was new stripe rust resistance gene(s) on S. africanum 2R^a. LF24 is a new substitution line which can be used as stripe rust resistant source in wheat improvement.     

Competitive binding of Fe<Superscript>3+</Superscript>, Cr<Superscript>3+</Superscript>, and Ni<Superscript>2+</Superscript> to transferrin

Competitive binding of Fe³⁺, Cr³⁺, and Ni²⁺ to transferrin (Tf) was investigated at various physiological iron to Tf concentration ratios. Loading percentages for these metal ions are based on a two M ⁿ⁺ to one Tf (i.e., 100% loading) stoichiometry and were determined using a particle beam/hollow cathode–optical emission spectroscopy (PB/HC-OES) method. Serum iron concentrations typically found in normal, iron-deficient, iron-deficient from chronic disease, iron-deficient from inflammation, and iron-overload conditions were used to determine the effects of iron concentration on iron loading into Tf. The PB/HC-OES method allows the monitoring of metal ions in competition with Fe³⁺ for Tf binding. Iron-overload concentrations impeded the ability of chromium (15.0 μM) or nickel (10.3 μM) to load completely into Tf. Low Fe³⁺ uptake by Tf under iron-deficient or chronic disease iron concentrations limited Ni²⁺ loading into Tf. Competitive binding kinetic studies were performed with Fe³⁺, Cr³⁺, and Ni²⁺ to determine percentages of metal ion uptake into Tf as a function of time. The initial rates of Fe³⁺ loading increased in the presence of nickel or chromium, with maximal Fe³⁺ loading into Tf in all cases reaching approximately 24%. Addition of Cr³⁺ to 50% preloaded Fe³⁺–Tf showed that excess chromium (15.0 μM) displaced roughly 13% of Fe³⁺ from Tf, resulting in 7.6 ± 1.3% Cr³⁺ loading of Tf. The PB/HC-OES method provides the ability to monitor multiple metal ions competing for Tf binding and will help to understand metal competition for Tf binding.     

Dynamic Changes of CD4<Superscript>+</Superscript>CD25<Superscript>+</Superscript> Regulatory T Cells in NOD.H-2<Superscript>h4</Superscript> Mice with Iodine-Induced Autoimmune Thyroiditis

Iodine is an essential trace element for thyroid hormone synthesis and metabolism, either low or high intake may lead to thyroid disease, but the pathogenetic mechanisms by which iodine interacts with the thyroid autoimmune are poorly understood. We investigated the dynamic changes of CD4⁺CD25⁺ regulatory T cells in NOD.H-2^h4 mice with iodine-induced autoimmune thyroiditis (AIT), and explore potential immune mechanism of AIT induced by iodine. NOD.H-2^h4 mice were randomly divided into two groups, and received plain water or water containing 0.005% sodium iodide. Eight weeks after iodine provision, the incidences of thyroiditis, relative weights of thyroids, and serum thyroglobulin antibody titers in the iodine-supplied groups were significantly increased compared to the control groups (p < 0.05). The AIT mice had fewer CD4⁺CD25⁺Foxp3⁺ T cells and reduced Foxp3 mRNA expression in splenocytes compared with the controls (p < 0.01), and maintained relatively low levels during the development of thyroiditis. The changes described above aggravated gradually with the extension of iodine treatment. These data suggest that CD4⁺CD25⁺ regulatory T cells may be involved in the pathogenesis and development of AIT induced by iodine.     

Measurement of activity concentrations of <Superscript>40</Superscript>K, <Superscript>226</Superscript>Ra and <Superscript>232</Superscript>Th for assessment of radiation hazards from soils of the southwestern region of Nigeria

Activity concentrations of the selected radionuclides ⁴⁰K, ²²⁶Ra and ²³²Th were measured in surface soil samples collected from 38 cities in the southwest region of Nigeria by means of gamma spectroscopy with a high-purity germanium detector. Measured activity concentration values of ⁴⁰K varied from 34.9 ± 4.4 to 1,358.6 ± 28.5 Bq kg⁻¹ (given on a dry mass (DM) basis) with a mean value of 286.5 ± 308.5 Bq kg⁻¹; that of ²²⁶Ra varied from 9.3 ± 3.7 to 198.1 ± 13.8 Bq kg⁻¹ with a mean value of 54.5 Bq kg⁻¹ and a standard deviation of 38.7 Bq kg⁻¹, while that of ²³²Th varied from 5.4 ± 1.1 to 502.0 ± 16.5 Bq kg⁻¹ with a mean value of 91.1 Bq kg⁻¹ and standard deviation of 100.9 Bq kg⁻¹. The mean activity concentration values obtained for ²²⁶Ra and ²³²Th are greater than the world average values reported by the United Nations Scientific Committee on Effects of Atomic Radiation for areas of normal background radiation. Radiological indices were estimated for the radiation/health hazards of the natural radioactivity of all soil samples. Estimated absorbed dose rates in air varied from 12.42 ± 2.25 to 451.33 ± 19.06 nGy h⁻¹, annual outdoor effective dose rates from 0.015 ± 0.003 to 0.554 ± 0.023 mSv year⁻¹, internal hazard index from 0.10 ± 0.03 to 3.02 ± 0.16, external hazard index from 0.07 ± 0.01 to 2.60 ± 0.11, representative level index from 0.19 ± 0.03 to 6.84 ± 0.29, activity index from 0.09 ± 0.02 to 3.42 ± 0.15, and radium equivalent activity from 26.95 ± 5.04 to 963.15 ± 41.87 Bq kg⁻¹. Only the mean value of the representative level index exceeds the limit for areas of normal background radiation. All other indices show mean values that are lower than the recommended limits.     

The control of CD4<Superscript>+</Superscript>CD25<Superscript>+</Superscript>Foxp3<Superscript>+</Superscript>regulatory T cell survival

   

CD4⁺CD25⁺Foxp3⁺ regulatory T (T_reg) cells are believed to play an important role in suppressing autoimmunity and maintaining peripheral tolerance. How their survival is regulated in the periphery is less clear. Here we show that T_reg cells express receptors for gamma chain cytokines and are dependent on an exogenous supply of these cytokines to overcome cytokine withdrawal apoptosis in vitro. This result was validated in vivo by the accumulation of T_reg cells in Bim^-/- and Bcl-2 tg mice which have arrested cytokine deprivation apoptosis. We also found that CD25 and Foxp3 expression were down-regulated in the absence of these cytokines. CD25⁺ cells from Scurfy mice do not depend on cytokines for survival demonstrating that Foxp3 increases their dependence on cytokines by suppressing cytokine production in T_reg cells. Our study reveals that the survival of T_reg cells is strictly dependent on cytokines and cytokine producing cells because they do not produce cytokines. Our study thus, demonstrates that different gamma chain cytokines regulate T_reg homeostasis in the periphery by differentially regulating survival and proliferation. These findings may shed light on ways to manipulate T_reg cells that could be utilized for their therapeutic applications.     

Regulatory role of E-NTPase/E-NTPDase in Ca<Superscript>2+</Superscript>/Mg<Superscript>2+</Superscript> transport via gated channel

Background  

E-NTPase/E-NTPDase is activated by millimolar concentrations of Ca²⁺ or Mg²⁺ with a pH optimum of 7.5 for the hydrolysis of extracellular NTP and NDP. It has been generally accepted that E-NTPase/E-NTPDase plays regulatory role in purinergic signalling, but other functions may yet be discovered.     

Enhanced anti-tumor activity of interferon-alpha in SOCS1-deficient mice is mediated by CD4<Superscript>+</Superscript> and CD8<Superscript>+</Superscript> T cells

Interferon-alpha (IFN-α) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant setting. The cellular actions of IFN-α are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We hypothesized that the anti-tumor activity of exogenous IFN-α would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1^−/−) or control (SOCS1^+/+) mice on an IFN-γ^−/− C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1^+/+ mice receiving IFN-A/D had significantly enhanced survival versus PBS–treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1^−/− mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1^−/− mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8⁺ T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1^−/− mice as compared with mice receiving a control antibody (P = 0.0021). CD4⁺ T-cell depletion from SOCS1^−/− mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1^+/+ or SOCS1^−/− mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1^+/+ or SOCS1^−/− mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor effects of IFN-α in the setting of melanoma.     

Metabolic trajectories based on <Superscript>1</Superscript>H NMR spectra of urines from sheep exposed to nutritional challenges during prenatal and early postnatal life

¹H NMR metabolic profiles of urine from sheep exposed to prenatal nutritional restriction (n = 19) and a control group with normal prenatal nutritional requirements (n = 19), followed by either conventional (n = 10 + 10) or high carbohydrate high fat postnatal diet (n = 9 + 9), were studied. Urine was sampled from 2, 6, 19 and 24-month-old animals receiving differential dietary treatments during the first 6 months and the same normal diet later. Principal component analysis of ¹H NMR spectra (n = 164) showed a V-shaped metabolic trajectory as a function of age and diet, starting with urines with a high amount of glucose, indicative of monogastric-like metabolism, and exhibiting concomitant increase of metabolites related to rumen microflora (mainly glycine conjugates of benzoic and phenylacetic acid) as the ruminal metabolism developed. Urines from young (2-month-old) animals exposed to prenatal undernutrition followed by normal postnatal diet showed metabolic patters that are ahead in time on the metabolic trajectory relative to the prenatal control group. No long-term effects of fetal undernutrition, alone or in combination with postnatal hypernutrition were observed.