Insights into the Structures of Bilirubin and Biliverdin from Vibrational and Electronic Circular Dichroism: History and Perspectives

: In this work we review research activities on a few of the most relevant structural aspects of bilirubin (BR) and biliverdin (BV). Special attention is paid to the exocyclic C=C bonds being in mostly Z rather than E configurations, and to the overall conformation being essentially different for BR and BV due to the presence or absence of the double C=C bond at C-10. In both cases, racemic mixtures of each compound of either M or P configuration are present in achiral solutions; however, imbalance between the two configurations may be easily achieved. In particular, results based on chiroptical spectroscopies, both electronic and vibrational circular dichroism (ECD and VCD) methods, are presented for chirally derivatized BR and BV molecules. Finally, we review deracemization experiments monitored with ECD data from our lab for BR in the presence of serum albumin and anesthetic compounds

Paediatric HIV and elimination of mother-to-child transmission of HIV in the ASEAN region: a call to action

Recent achievements in scaling up paediatric antiretroviral therapy (ART) have changed the life of children living with HIV, who now stay healthy and live longer lives. However, as it becomes more of a chronic infection, a range of new problems have begun to arise. These include the disclosure of HIV serostatus to children, adherence to ART, long-term toxicities of antiretroviral drugs and their sexual and reproductive health, which are posing significant challenges to the existing health systems caring for children with HIV with limited resources, experiences and capacities. While intensified efforts and actions to improve care and treatment for these children are needed, it is crucial to accelerate the prevention of mother-to-child transmission (PMTCT) of HIV, which is the main cause of paediatric HIV in the ASEAN region so as to eliminate the fundamental cause of the problem. This report argues that given over 70% of women have access to at least one antenatal care visit in the region and acceptance of HIV testing after receiving counselling on PMTCT could be as high as 90%, there is an opportunity to strengthen PMTCT services and eventually eliminate new paediatric HIV infections in the ASEAN countries

Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system

Functionally and spatially distinct PI 3-K pathways act either early to promote myelination downstream of axonal Neuregulin1 or late to inhibit myelination downstream of α6β4 integrin and Sgk1

Experiences from two ways of integrating Pre- and Post-course Multiple-choice assessment questions in educational events for surgeons

To examine how to optimise the integration of multiple-choice questions (MCQs) for learning in continuing professional development (CPD) events in surgery, we implemented and evaluated two methods in two subspecialities over multiple years. The same 12 MCQs were administered pre- and post-event in 66 facial trauma courses. Two different sets of 10 MCQs were administered pre- and post-event in 21 small animal fracture courses. We performed standard psychometric tests on responses from participants who completed both the pre- and post-event assessment. The average difficulty index pre-course was 57% with a discrimination index of 0.20 for small animal fractures and 53% with a discrimination index of 0.15 for facial trauma. For the majority of the individual MCQs, the scores were between 30%-70% and the discrimination index was >0.10. The difficulty index post-course increased in both groups (to 75% and 62%). The pre-course MCQs resulted in an average score in the expected range for both formats suggesting they were appropriate for the intended level of difficulty and an appropriate pre-course learning activity. Post-course completion resulted in increased scores with both formats. Both delivery methods worked well in all regions and overall quality depends on applying a solid item development and validation process

Hepatitis C virus and alcohol: Same mitotic targets but different signaling pathways

Background & Aims: Chromosomal aberrations are frequently observed in hepatitis C virus (HCV)- and alcohol-related hepatocellular carcinomas (HCCs). The mechanisms by which chromosomal aberrations occur during hepatocarcinogenesis are still unknown. However, these aberrations are considered to be the result of deregulation of some mitotic proteins, including the alteration of Cyclin B1 and Aurora kinase A expression, and the phosphorylation of gamma-tubulin. Our study aims at investigating changes in expression of the above mentioned proteins and related intracellular pathways, in in vitro and in vivo models of both HCV- and alcohol- dependent HCCs.Methods: In this study, the molecular defects and the mechanisms involved in deregulation of the mitotic machinery were analyzed in human hepatoma cells, expressing HCV proteins treated or not with ethanol, and in liver tissues from control subjects (n = 10) and patients with HCV- (n = 10) or alcohol-related (n = 10) HCCs.Results: Expression of Cyclin B1, Aurora kinase A, and tyrosine-phosphorylated gamma-tubulin was analyzed in models reproducing HCV infection and ethanol treatment in HCC cells. Interestingly, HCV and alcohol increased the expression of Cyclin B, Aurora kinase A, and tyrosine-phosphorylated gamma-tubulin also in tissues from patients with HCV- or alcohol-related HCCs. In vitro models suggest that HCV requires the expression of PKR (RNA-activated protein kinase), as well as JNK (c-Jun N-terminal kinase) and p38MAPK (p38 mitogen-activated protein kinase) proteins; while, ethanol bypasses all these pathways.Conclusions: Our results support the idea that HCV and alcohol may promote oncogenesis by acting through the same mitotic proteins, but via different signaling pathways. (C) 2011 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver

L-Stercobilin-HCl and d-Urobilin-HCl. Analysis of Their Chiroptical and Conformational Properties by VCD, ECD, and CPL Experiments and MD and DFT Calculations

Vibrational circular dichroism (CD) and IR spectra of dichloromethane solutions of l-stercobilin and d-urobilin hydrochlorides have been recorded in the mid-IR region. The spectra are best interpreted by combining molecular dynamics calculations and density functional theory (DFT) calculations within the quantum mechanics/molecular mechanics ONIOM-type framework, and the combined predicted results are better and more informative than the more standard analysis provided by DFT calculations. The same approach also sheds light on the Cotton effect sign inversion of room temperature versus low-temperature electronic CD spectra of the same compounds in methanol–glycerol solution. Finally, circularly polarized luminescence spectra for l-stercobilin in chloroform solution provide information on the excited-state geometry of this molecule

Passive sentinel surveillance system for sexually transmitted diseases in primary healthcare sites in Ethiopia, 1991–3

Background: In 1989 the ministry of health of Ethiopia launched an STD control programme to strengthen the STD case management capabilities at public health centres and hospitals. The programme included the introduction of a syndrome based system for notification of STD cases. We here report the data originated by the syndromic case reporting system under programme conditions. Methods: 35 (17%) of the total 225 hospitals and public health centres of Ethiopia were included in the programme. Information relevant to the years 1991 to 1993 was analysed at mid 1994. Results: 32 clinical sites (91% of the total) provided at least one monthly report. The proportion of monthly reports received was 65% of those due, ranging from 51% in 1991 to 73% in 1992 and 42% in 1993. A total of 77 294 consultations for STD related symptoms were recorded, including 70 200 new cases, 6588 repeated consultations, and 506 partners of STD patients. Among first attendant patients 38 459 (52.7%) were males with a male to female ratio of 1:1. Urethral discharge and vaginal discharge were the leading cause of consultation among males (58%) and females (64%) respectively. The frequency of genital ulcer diseases was 26% among males and 15% among females. Inguinal adenopathy in the absence of genital ulcers was also frequent, accounting for 10% of consulting males and 5% of females. Based on Gram stain, gonorrhoea was identified in 64% of the cases of urethral discharge, while trichomoniasis and candidiasis were identified by wet mount in 28% and 16% of the cases of vaginal discharge respectively. Conclusions: STDs are a common cause of consultation at public health centre sites in Ethiopia. A syndromic case reporting system proved to be efficient and produced valuable information to initiate assessment of the problem and to set up bases for monitoring trends of STD morbidity. Key Words: sexually transmitted diseases; case notification; Ethiopi

Bilirubin and its congeners: conformational analysis and chirality from metadynamics and related computational methods

The conformational properties of natural bilirubin, bisbutyricmesobilirubin-XIIIα, and their chiral derivatives (βS,β′S)- dimethylmesobilirubin-XIIIα and 8,12-(γR,γ′R)- dimethylbisbutyricmesobilirubin-XIIIα were investigated by metadynamics, an improved molecular dynamics computational methodology useful for conformational analysis. Applied to linear tetrapyrroles, which may be treated as two blade molecular propellers, our results are represented by conformational energy hypersurface maps built as functions of the two central dihedral torsion angles (φ1 and φ2) following rotations of two dipyrrinone units about the connecting CH2, and are compared successfully with maps previously obtained from molecular mechanics. With an emphasis on the conformationally more flexible 8,12-(γR,γ′R)-dimethylbisbutyricmesobilirubin-XIIIα, a conformationally mobile optically active bilirubinoid with butyric acid replacing propionic, metadynamics reveals global and nearby minima. Its electronic circular dichroism and UV–Vis spectra predicted by DFT calculations correlate well with the experimental spectra and are explained on the basis of equilibrium between the predicted conformational energy minima