Therapeutic Radionuclides: Making the Right Choice

Recently, there has been a resurgence of interest in nuclear medicine therapeutic procedures. Using unsealed sources for therapy is not a new concept; it has been around since the beginnings of nuclear medicine. Treatment of thyroid disorders with radioiodine is a classic example. The availability of radionuclides with suitable therapeutic properties for specific applications, as well as methods for their selective targeting to diseased tissue have, however, remained the main obstacles for therapy to assume a more widespread role in nuclear medicine. Nonetheless, a number of new techniques that have recently emerged, (e.g., tumor therapy with radiolabeled monoclonal antibodies, treatment of metastatic bone pain, etc.) appear to have provided a substantial impetus to research on production of new therapeutic radionuclides. Although there are a number of new therapeutic approaches requiring specific radionuclides, only selected broad areas will be used as examples in this article

Sleep duration, vital exhaustion and perceived stress among pregnant migraineurs and non-migraineurs

<p>Abstract</p> <p>Background</p> <p>Migraine has been associated with sleep disorders in men and non-pregnant women, but little is known about sleep complaints among pregnant migraineurs.</p> <p>Methods</p> <p>A cohort of 1,334 women was interviewed during early pregnancy. At the time of interview we ascertained participants' migraine diagnosis status and collected information about sleep duration before and during early pregnancy, daytime sleepiness, vital exhaustion and perceived stress during early pregnancy. Multivariable logistic regression procedures were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of short/long sleep duration, excessive daytime sleepiness, vital exhaustion and elevated perceived stress associated with a history of migraine.</p> <p>Results</p> <p>Approximately 19.4% of the cohort (n = 259) reported having a medical diagnosis of migraine prior to the study pregnancy. Compared with women without migraine, the multivariable-adjusted ORs (95% CI) among migraineurs for short sleep duration before and during early pregnancy were 1.51 (1.09-2.09), and 1.57 (1.11-2.23), respectively. The corresponding OR (95% CI) for long sleep duration before and during pregnancy were 1.33 (0.77-2.31) and 1.31 (0.94-1.83), respectively. A modest and statistically insignificant association between migraine history and excessive daytime sleepiness in early pregnancy was noted (OR = 1.46; 95% CI 0.94-2.26). Migraineurs had an increased risk of vital exhaustion (OR = 2.04; 95% CI 1.52-2.76) and elevated perceived stress (OR = 1.57; 95% CI 1.06-2.31). Observed associations were more pronounced among overweight migraineurs.</p> <p>Conclusions</p> <p>These data support earlier research documenting increased risks of sleep disorders among migraineurs; and extends the literature to include pregnant women. Prospective studies are needed to more thoroughly explore factors that mediate the apparent migraine-sleep comorbidity among pregnant women.</p

Impact of today's media on university student's body image in Pakistan: a conservative, developing country's perspective

<p>Abstract</p> <p>Background</p> <p>Living in a world greatly controlled by mass media makes it impossible to escape its pervading influence. As media in Pakistan has been free in the true sense of the word for only a few years, its impact on individuals is yet to be assessed. Our study aims to be the first to look at the effect media has on the body image of university students in a conservative, developing country like Pakistan. Also, we introduced the novel concept of body image dissatisfaction as being both negative and positive.</p> <p>Methods</p> <p>A cross-sectional study was conducted among 7 private universities over a period of two weeks in the city of Karachi, Pakistan's largest and most populous city. Convenience sampling was used to select both male and female undergraduate students aged between 18 and 25 and a sample size of 783 was calculated.</p> <p>Results</p> <p>Of the 784 final respondents, 376 (48%) were males and 408 (52%) females. The mean age of males was 20.77 (+/- 1.85) years and females was 20.38 (+/- 1.63) years. Out of these, 358 (45.6%) respondents had a positive BID (body image dissatisfaction) score while 426 (54.4%) had a negative BID score. Of the respondents who had positive BID scores, 93 (24.7%) were male and 265 (65.0%) were female. Of the respondents with a negative BID score, 283 (75.3%) were male and 143 (35.0%) were female. The results for BID vs. media exposure were similar in both high and low peer pressure groups. Low media exposure meant positive BID scores and vice versa in both groups (p < 0.0001) showing a statistically significant association between high media exposure and negative body image dissatisfaction. Finally, we looked at the association between gender and image dissatisfaction. Again a statistically significant association was found between positive body image dissatisfaction and female gender and negative body image dissatisfaction and male gender (p < 0.0001).</p> <p>Conclusions</p> <p>Our study confirmed the tendency of the media to have an overall negative effect on individuals' body image. A striking feature of our study, however, was the finding that negative body image dissatisfaction was found to be more prevalent in males as compared to females. Likewise, positive BID scores were more prevalent amongst females.</p

Increased Resting-State Functional Connectivity in Obese Adolescents; A Magnetoencephalographic Pilot Study

BACKGROUND: Obesity is not only associated with metabolic abnormalities, but also with cognitive dysfunction and changes in the central nervous system. The present pilot study was carried out to investigate functional connectivity in obese and non-obese adolescents using magnetoencephalography (MEG). METHODOLOGY/PRINCIPAL FINDINGS: Magnetoencephalographic recordings were performed in 11 obese (mean BMI 38.8+/-4.6 kg/m(2)) and 8 lean (mean BMI 21.0+/-1.5 kg/m(2)) female adolescents (age 12-19 years) during an eyes-closed resting-state condition. From these recordings, the synchronization likelihood (SL), a common method that estimates both linear and non-linear interdependencies between MEG signals, was calculated within and between brain regions, and within standard frequency bands (delta, theta, alpha1, alpha2, beta and gamma). The obese adolescents had increased synchronization in delta (0.5-4 Hz) and beta (13-30 Hz) frequency bands compared to lean controls (P(delta total) = 0.001; P(beta total) = 0.002). CONCLUSIONS/SIGNIFICANCE: This study identified increased resting-state functional connectivity in severe obese adolescents. Considering the importance of functional coupling between brain areas for cognitive functioning, the present findings strengthen the hypothesis that obesity may have a major impact on human brain function. The cause of the observed excessive synchronization is unknown, but might be related to disturbed motivational pathways, the recently demonstrated increase in white matter volume in obese subjects or altered metabolic processes like hyperinsulinemia. The question arises whether the changes in brain structure and communication are a dynamic process due to weight gain and whether these effects are reversible or not

SirT1 modulates the estrogen–insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice

INTRODUCTION: Estrogen and insulin-like growth factor-1 (IGF-1) play important roles in mammary gland development and breast cancer. SirT1 is a highly conserved protein deacetylase that can regulate the insulin/IGF-1 signaling in lower organisms, as well as a growing number of transcription factors, including NF-κB, in mammalian cells. Whether SirT1 regulates the IGF-1 signaling for mammary gland development and function, however, is not clear. In the present study, this role of SirT1 was examined by studying SirT1-deficient mice. METHODS: SirT1-deficient (SirT1(ko/ko)) mice were generated by crossing a new strain of mice harboring a conditional targeted mutation in the SirT1 gene (SirT1(co/co)) with CMV-Cre transgenic mice. Whole mount and histology analyses, immunofluorescence staining, immunohistochemistry, and western blotting were used to characterize mammary gland development in virgin and pregnant mice. The effect of exogenous estrogen was also examined by subcutaneous implantation of a slow-releasing pellet in the subscapular region. RESULTS: Both male and female SirT1(ko/ko )mice can be fertile despite the growth retardation phenotype. Virgin SirT1(ko/ko )mice displayed impeded ductal morphogenesis, whereas pregnant SirT1(ko/ko )mice manifested lactation failure due to an underdeveloped lobuloalveolar network. Estrogen implantation was sufficient to rescue ductal morphogenesis. Exogenous estrogen reversed the increased basal level of IGF-1 binding protein-1 expression in SirT1(ko/ko )mammary tissues, but not that of IκBα expression, suggesting that increased levels of estrogen enhanced the production of local IGF-1 and rescued ductal morphogenesis. Additionally, TNFα treatment enhanced the level of the newly synthesized IκBα in SirT1(ko/ko )cells. SirT1 deficiency therefore affects the cellular response to multiple extrinsic signals. CONCLUSION: SirT1 modulates the IGF-1 signaling critical for both growth regulation and mammary gland development in mice. SirT1 deficiency deregulates the expression of IGF-1 binding protein-1 and attenuates the effect of IGF-1 signals, including estrogen-stimulated local IGF-1 signaling for the onset of ductal morphogenesis. These findings suggest that the enzymatic activity of SirT1 may influence both normal growth and malignant growth of mammary epithelial cells

Subtype-associated differences in HIV-1 reverse transcription affect the viral replication

Background: The impact of the products of the pol gene, specifically, reverse transcriptase (RT) on HIV-1 replication, evolution, and acquisition of drug resistance has been thoroughly characterized for subtype B. For subtype C, which accounts of almost 60% of HIV cases worldwide, much less is known. It has been reported that subtype C HIV-1 isolates have a lower replication capacity than B; however, the basis of these differences remains unclear. Results: We analyzed the impact of the pol gene products from HIV-1 B and C subtypes on the maturation of HIV virions, accumulation of reverse transcription products, integration of viral DNA, frequency of point mutations in provirus and overall viral replication. Recombinant HIV-1 viruses of B and C subtypes comprising the pol fragments encoding protease, integrase and either the whole RT or a chimeric RT from different isolates of the C and B subtypes, were used for infection of cells expressing CXCR4 or CCR5 co-receptors. The viruses carrying different fragments of pol from the isolates of B and C subtypes did not reveal differences in Gag and GagPol processing and viral RNA incorporation into the virions. However, the presence of the whole RT from subtype C, or the chimeric RT containing either the polymerase or the connection and RNase H domains from C isolates, caused significantly slower viral replication regardless of B or C viral backbone. Subtype C RT carrying viruses displayed lower levels of accumulation of strong-stop cDNA in permeabilized virions during endogenous reverse transcription, and decreased accumulation of both strong-stop and positive strand reverse transcription products in infected cells and in isolated reverse transcription complexes. This decreased accumulation correlated with lower levels of viral DNA integration in cells infected with viruses carrying the whole RT or RT domains from subtype C isolates. The single viral genome assay analysis did not reveal significant differences in the frequency of point mutations between the RT from B or C subtypes. Conclusions: These data suggest that the whole RT as well as distinct polymerase and connection-RNase H domains from subtype C HIV-1 confer a lower level of accumulation of reverse transcripts in the virions and reverse transcription complexes as compared to subtype B, resulting in a lower overall level of virus replication

Physical Analyses of E. coli Heteroduplex Recombination Products In Vivo: On the Prevalence of 5′ and 3′ Patches

BACKGROUND: Homologous recombination in Escherichia coli creates patches (non-crossovers) or splices (half crossovers), each of which may have associated heteroduplex DNA. Heteroduplex patches have recombinant DNA in one strand of the duplex, with parental flanking markers. Which DNA strand is exchanged in heteroduplex patches reflects the molecular mechanism of recombination. Several models for the mechanism of E. coli RecBCD-mediated recombinational double-strand-end (DSE) repair specify that only the 3'-ending strand invades the homologous DNA, forming heteroduplex in that strand. There is, however, in vivo evidence that patches are found in both strands. METHODOLOGY/PRINCIPLE FINDINGS: This paper re-examines heteroduplex-patch-strand polarity using phage lambda and the lambdadv plasmid as DNA substrates recombined via the E. coli RecBCD system in vivo. These DNAs are mutant for lambda recombination functions, including orf and rap, which were functional in previous studies. Heteroduplexes are isolated, separated on polyacrylamide gels, and quantified using Southern blots for heteroduplex analysis. This method reveals that heteroduplexes are still found in either 5' or 3' DNA strands in approximately equal amounts, even in the absence of orf and rap. Also observed is an independence of the RuvC Holliday-junction endonuclease on patch formation, and a slight but statistically significant alteration of patch polarity by recD mutation. CONCLUSIONS/SIGNIFICANCE: These results indicate that orf and rap did not contribute to the presence of patches, and imply that patches occurring in both DNA strands reflects the molecular mechanism of recombination in E. coli. Most importantly, the lack of a requirement for RuvC implies that endonucleolytic resolution of Holliday junctions is not necessary for heteroduplex-patch formation, contrary to predictions of all of the major previous models. This implies that patches are not an alternative resolution of the same intermediate that produces splices, and do not bear on models for splice formation. We consider two mechanisms that use DNA replication instead of endonucleolytic resolution for formation of heteroduplex patches in either DNA strand: synthesis-dependent-strand annealing and a strand-assimilation mechanism

HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells

INTRODUCTION: Amplification of the HER-2 receptor tyrosine kinase has been implicated in the pathogenesis and aggressive behavior of approximately 25% of invasive human breast cancers. Clinical and experimental evidence suggest that aberrant HER-2 signaling contributes to tumor initiation and disease progression. Transforming growth factor beta (TGF-β) is the dominant factor opposing growth stimulatory factors and early oncogene activation in many tissues, including the mammary gland. Thus, to better understand the mechanisms by which HER-2 overexpression promotes the early stages of breast cancer, we directly assayed the cellular and molecular effects of TGF-β1 on breast cancer cells in the presence or absence of overexpressed HER-2. METHODS: Cell proliferation assays were used to determine the effect of TGF-β on the growth of breast cancer cells with normal or high level expression of HER-2. Affymetrix microarrays combined with Northern and western blot analysis were used to monitor the transcriptional responses to exogenous TGF-β1 in luminal and mesenchymal-like breast cancer cells. The activity of the core TGF-β signaling pathway was assessed using TGF-β1 binding assays, phospho-specific Smad antibodies, immunofluorescent staining of Smad and Smad DNA binding assays. RESULTS: We demonstrate that cells engineered to over-express HER-2 are resistant to the anti-proliferative effect of TGF-β1. HER-2 overexpression profoundly diminishes the transcriptional responses induced by TGF-β in the luminal MCF-7 breast cancer cell line and prevents target gene induction by a novel mechanism that does not involve the abrogation of Smad nuclear accumulation, DNA binding or changes in c-myc repression. Conversely, HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-β induced pro-invasive and pro-metastatic gene signature. CONCLUSION: HER-2 overexpression promotes the growth and malignancy of mammary epithelial cells, in part, by conferring resistance to the growth inhibitory effects of TGF-β. In contrast, HER-2 and TGF-β signaling pathways can cooperate to promote especially aggressive disease behavior in the context of a highly invasive breast tumor model