Retinoic acid conjugates as potential antitumor agents: synthesis and biological activity of conjugates with Ara-A, Ara-C, 3(2H)-furanone, and aniline mustard moieties

In a dual targeting approach, to explore the ability of tretinoin (all-trans-retinoic acid) to behave as a covalent carrier for cytotoxic entities, conjugates of retinoic acid with a few representative molecules, being important examples of antitumor pharmacophores (i.e., nucleoside analogues and alkylating agents), have been synthesized and tested for their cytostatic and differentiating activity. All compounds were stable to in vitro hydrolysis in human plasma and more lipophilic than the parent compounds, thus consenting enhanced uptake into the cells. Among the nucleoside analogues the Ara-C derivatives 3 and 6 and the Ara-A derivative 7 proved the most cytostatic (IC50 < 0.32 microgram/mL) resulting from 25- to > 144-fold more active (Ara-A derivatives) or at least as equally active (Ara-C derivatives) as compared to the parent nucleosides. Compound 3, endowed with a highly lipophilic silyl moiety at the 3' and 5' positions, showed the highest differentiating activity (54% and 44% differentiated HL-60 cells at 0.2 and 0.05 microgram/mL respectively). With regard to the retinoic acid conjugates of alkylating agents, compound 10 was the most cytostatic agent (IC50 < 0.32 microgram/mL) and the most potent differentiating agent (33-34% at 0.32 and 0.08 microgram/mL). These structures may also be regarded as analogs of either retinoic acid or the cytotoxic compound.     

The Contribution of Small Vessel Disease to Neurodegeneration: Focus on Alzheimer’s Disease,Parkinson’s Disease and Multiple Sclerosis

Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology of central nervous system (CNS) neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD), and neuroinflammatory diseases, such as multiple sclerosis (MS). These disorders share different pathophysiological pathways and molecular mechanisms (i.e., protein misfolding, derangement of cellular clearance systems, mitochondrial impairment and immune system activation) having neurodegeneration as biological outcome. In these diseases, the actual contribution of SVD to the clinical picture, and its impact on response to pharmacological treatments, is not known yet. Due to the high frequency of SVD in adult-aged patients, it is important to address this issue. In this review, we report preclinical and clinical data on the impact of SVD in AD, PD and MS, with the main aim of clarifying the predictability of SVD on clinical manifestations and treatment response.     

Effect of neighbouring village conditions and infrastructure interdependency on economic opportunity: A case study of the Yogyakarta region,Indonesia

To determine whether the inclusion of conditions in neighbouring villages and infrastructure interdependency are able to improve the performance of infrastructure–economy interaction models, we compare three related and progressive concepts. The first concept defines economic opportunity in a village as a function of available infrastructure within that village. The second concept includes the effect of economic opportunity in neighbouring villages in addition to available infrastructure within the village. In the third concept, we include the interdependency of infrastructures as another factor affecting the potential level of economic development in the village. We use Ordinary Least Squares (OLS) and a Geographic Information System (GIS) to model the first concept, and we add a spatial-lag model for the second. The third model expands on the second by introducing a Sugeno Fuzzy Inference System (FIS) and a rule-based OLS to capture the nature of infrastructure interdependency. The result of the three models is validated by a known spatial distribution of poverty levels and subjective well-being that serve as proxies for economic opportunity in the Yogyakarta region in Indonesia. The results demonstrate that the third model provides a more accurate prediction of the real conditions and performs consistently better than the other two models. We therefore conclude that conditions in neighbouring villages and infrastructure interdependency influence the economic opportunity of a village and should be considered in policy making regarding resource allocation in infrastructure development.     

Changes in endocrine profile and reproductive organs during puberty in the male marmoset monkey (Callithrix jacchus)

Data on pubertal maturation in male marmoset, a model for human reproduction, are scant and conflicting. We collected data on novel parameters to characterize puberty. Twenty-five marmoset monkeys were assigned to five age groups by weeks (wk): 21 (pre-pubertal), 43 (onset of puberty), 52 (fully pubertal), 70 (mature), and 116 (fully adult). Serum and intratesticular testosterone and pituitary bioactive chorionic gonadotropin (bioCG) were measured. Testicular development was assessed by ultrasonography, histology, and flow cytometry. Three consecutive blood samples revealed extreme fluctuations in testosterone concentrations, suggesting an erratic secretion. Age-related changes in serum testosterone and pituitary bioCG concentrations were observed. Intratesticular androgens (ITAs) showed high fluctuations within groups at all ages and were high in some animals by 21 wk. Unexpectedly, no correlation between pituitary bioCG and serum testosterone or ITAs was found, but these parameters significantly correlated with testicular weight and volume. These observations were consistent a dependence on the testis growth on bioCG. Unfortunately, the low serum levels of bioCG were not measurable in this study. At 43 wk, the animals reached puberty. At 52 wk of age, animals attained maximum body and epididymal weights and qualitatively normal spermatogenesis, but testes continued growing, reaching a maximum of all parameters at 70 wk of age, without further major changes at the age of 116 wk. It is concluded that (1) gonadal activation is evident at wk 21, (2) the male marmoset reaches the pubertal threshold around 43 wk of age, attains qualitative parameters at 52 wk, matures further to sexual maturity at 70 wk, and (3) serum testosterone and ITAs are highly variable without any identifiable correlation with pituitary bioCG.     

Vibrational and thermal study on the in vitro and in vivo degradation of a bioabsorbable periodontal membrane: Vicryl® Periodontal Mesh (Polyglactin 910)

Fourier transform Raman (FT-Raman), attenuated total reflection/Fourier transform infrared (ATR/FT-IR) spectra and differential scanning calorimetry (DSC) measurements were performed on a biodegradable periodontal membrane, the Vicryl® periodontal mesh, in order to study its in vitro and in vivo degradation mechanism and kinetics. The hydrolitic in vitro degradation was investigated in two aqueous media: a saline phosphate buffer (SPB, pH=7.4) and a 0.01 M NaOH solution. Moreover, a membrane implanted in vivo for 4 weeks for treatment of contiguous vertical bony defects, was examined. Vibrational and thermal measurements show that the Vicryl® membrane presents a semicrystalline structure. It degrades faster in the NaOH solution than in the SPB and degradation occurs heterogeneously with a progressive increase in the percentage of crystallinity and shortening of the polymeric chains both in vitro and in vivo. The trends of % weight loss and IR I₆₂₇/I₁₄₁₅ intensity ratio (identified as a marker of crystallinity) are discussed in comparison with the DSC results. The IR I₆₂₇/I₁₄₁₅ intensity ratio and X_c% allow to determine the % weight loss undergone by the membrane degraded in vivo. The result obtained shows that the Vicryl® membrane degrades faster in vivo than in vitro with the formation of oligomers which are more easily absorbed by the surrounding tissues than they are soluble in the degradation media examined.     

Bleeding fibroma of the small intestine

A case of serious, recurrent enterorrhagia is reported. The cause could not be identified with normal diagnostic tools and was discovered only after explorative laparotomy. The finding was benign ulcerated tumour of the small intestine, histologically defined as fibroma with fluorishing cellularity.     

An Integrated CMOS Front-End for Optical Absolute Rotary Encoders

This paper presents a front-end circuit for optical rotary encoders. The light pulses modulated by the encoder disc are transduced into current signals, which are pre-processed and converted into digital waveforms related to the disc angular position information. The proposed front-end circuit is compensated against temperature drifts. Digitally programmable calibration is provided to account for spreads in impinging light pulse power. Measurement results on integrated prototypes are shown, demonstrating correct operation of the front-end with an optical input power from 0.5 W to 3 W up to a signal frequency of 500 kHz in a temperature range from 0 °C to 80 °C.     

A randomized controlled trial of a peer support intervention targeting antiretroviral medication adherence and depressive symptomatology in HIV-positive men and women.

Objective: To determine the efficacy of a peer-led social support intervention involving support groups and telephone contacts compared with standard clinical care to enhance antiretroviral medication adherence. Design: Randomized controlled trial with follow-up. Participants were 136 HIV-positive indigent mainly African American and Puerto Rican men and women recruited from an outpatient clinic in the Bronx, New York. The 3-month intervention was delivered by other HIV-positive clinic patients trained in addressing barriers to adherence and sensitively providing appraisal, spiritual, emotional, and informational adherence-related social support. Main outcome measures: Medical chart-abstracted HIV-1 RNA viral load, antiretroviral adherence according to electronic drug monitoring and participant self-report, and social support and depressive symptomatology. All assessments conducted at baseline, 3 months, and 6 months. Results: Intent-to-treat and as-treated analyses indicated no between-conditions intervention effects on the primary outcome of HIV-1 RNA viral load or any of the secondary outcomes at immediate postintervention or follow-up. Post hoc analyses within the intervention condition indicated greater intervention exposure was associated with higher self-reported adherence, higher social support, and lower depressive symptomatology at follow-up, even after controlling for baseline adherence. Conclusion: Null findings, consistent with the limited literature on efficacious highly active antiretroviral therapy (HAART) adherence interventions, may be due to insufficient exposure to the intervention, its low intensity, or the nature of the sample-a heterogeneous HAART-experienced group of patients with high levels of substance use and multiple other competing stressors. Overall, findings highlight the need for more comprehensive and intensive efforts to battle nonadherence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)