Depressive disorders in caregivers of dementia patients: a systematic review.

Although depressive symptomatology has been well studied in caregivers of patients with dementia, depressive disorders have been examined much less. We conducted a systematic literature search in major bibliographical databases (Medline, Psychinfo, Dissertation Abstracts), and included studies examining caregivers of dementia patients that reported the prevalence of major depressive disorder, according to diagnostic criteria as assessed with a standardized psychiatric diagnostic interview. Ten studies with a total of 790 caregivers were identified (sample sizes: 22–147). In only one of the studies, a representative community sample was used. A total of 176 subjects (22.3%) had a depressive disorder (prevalence range from 0.15–0.32). In the three studies reporting differential prevalence rates for men and women somewhat smaller prevalence rates were found for men than for women. In six studies caregivers were compared to a (mostly matched) control group. The relative risks of having a depressive disorder in caregivers ranged from 2.80–38.68 (all RR’s were significant). In the three prospective studies relatively high incidence rates were found (0.48). This study made it clear that prevalence and incidence of depressive disorders are increased in caregivers of dementia patients. More research is clearly needed in this population

Identification and Correction of Mechanisms Underlying Inherited Blindness in Human iPSC-Derived Optic Cups

Leber congenital amaurosis (LCA) is an inherited retinal dystrophy that causes childhood blindness. Photoreceptors are especially sensitive to an intronic mutation in the cilia-related gene CEP290, which causes missplicing and premature termination, but the basis of this sensitivity is unclear. Here, we generated differentiated photoreceptors in three-dimensional optic cups and retinal pigment epithelium (RPE) from iPSCs with this common CEP290 mutation to investigate disease mechanisms and evaluate candidate therapies. iPSCs differentiated normally into RPE and optic cups, despite abnormal CEP290 splicing and cilia defects. The highest levels of aberrant splicing and cilia defects were observed in optic cups, explaining the retinal-specific manifestation of this CEP290 mutation. Treating optic cups with an antisense morpholino effectively blocked aberrant splicing and restored expression of full-length CEP290, restoring normal cilia-based protein trafficking. These results provide a mechanistic understanding of the retina-specific phenotypes in CEP290 LCA patients and potential strategies for therapeutic intervention

Localisation of RNAs into the germ plasm of vitellogenic xenopus oocytes

We have studied the localisation of mRNAs in full-grown Xenopus laevis oocytes by injecting fluorescent RNAs, followed by confocal microscopy of the oocyte cortex. Concentrating on RNA encoding the Xenopus Nanos homologue, nanos1 (formerly Xcat2), we find that it consistently localised into aggregated germ plasm ribonucleoprotein (RNP) particles, independently of cytoskeletal integrity. This implies that a diffusion/entrapment-mediated mechanism is active, as previously reported for previtellogenic oocytes. Sometimes this was accompanied by localisation into scattered particles of the “late”, Vg1/VegT pathway; occasionally only late pathway localisation was seen. The Xpat RNA behaved in an identical fashion and for neither RNA was the localisation changed by any culture conditions tested. The identity of the labelled RNP aggregates as definitive germ plasm was confirmed by their inclusion of abundant mitochondria and co-localisation with the germ plasm protein Hermes. Further, the nanos1/Hermes RNP particles are interspersed with those containing the germ plasm protein Xpat. These aggregates may be followed into the germ plasm of unfertilized eggs, but with a notable reduction in its quantity, both in terms of injected molecules and endogenous structures. Our results conflict with previous reports that there is no RNA localisation in large oocytes, and that during mid-oogenesis even germ plasm RNAs localise exclusively by the late pathway. We find that in mid oogenesis nanos1 RNA also localises to germ plasm but also by the late pathway. Late pathway RNAs, Vg1 and VegT, also may localise into germ plasm. Our results support the view that mechanistically the two modes of localisation are extremely similar, and that in an injection experiment RNAs might utilise either pathway, the distinction in fates being very subtle and subject to variation. We discuss these results in relation to their biological significance and the results of others

The Railway Line Frequency and Size Setting Problem

[EN] The problem studied in this paper takes as input data a set of lines forming a railway network, and an origin¿destination (OD) matrix. The OD pairs may use either the railway network or an alternative transportation mode. The objective is to determine the frequency/headway of each line as well as its number of carriages, so that the net profit of the railway network is maximized. We propose a mixed integer non-linear programming formulation for this problem. Because of the computational intractability of this model, we develop four algorithms: a mixed integer linear programming (MIP) model, a MIP-based iterative algorithm, a shortest-path based algorithm, and a local search. These four algorithms are tested and compared over a set of randomly generated instances. An application over a case study shows that only the local search heuristic is capable of dealing with large instances.This research was partly funded by the Canadian Natural Sciences and Engineering Research Council under Grant 2015-06189, by the Ministerio de Economía y Competitividad (Spain)/FEDER under projects MTM2012-37048, MTM2015-67706-P and DPI2012-36243-C02-01, and by Junta de Andalucía (Spain)/FEDER under excellence project P10-FQM-5849. Part of this research was done while Federico Perea was enjoying a research visit to CIRRELT, funded by the Universitat Politècnica de València, under program PAID-00-15. This support is gratefully acknowledged. Thanks are due to the referees for their valuable comments.De-Los-Santos, A.; Laporte, G.; Mesa, JA.; Perea Rojas Marcos, F. (2017). The Railway Line Frequency and Size Setting Problem. Public Transport. 9(1-2):33-53. https://doi.org/10.1007/s12469-017-0154-2S335391-2Albrecht T (2009) Automated timetable design for demand-oriented service on suburban railways. Public Transport 1(1):5–20Caprara A, Kroon L, Monaci M, Peeters M, Toth P (2007) Passenger Railway optimization. In: Barnhart C, Laporte G (eds) Handbooks in operations research and management science, vol 14. Transportation, chapter 3. North-Holland, Amsterdam, pp 129–187De-Los-Santos A, Laporte G, Mesa J, Perea F (2014) Simultaneous frequency and capacity setting in uncapacitated metro lines in presence of a competing mode. Transp Res Proc 3:289–298Desaulniers G, Hickman M (2007) Public transport. In: Barnhart C, Laporte G (eds) Handbook in operations research and management science, vol 14, Transportation, chapter 2. North-Holland, Amsterdam, pp 69–127Gallo M, Montella B, D’Acierno L (2011) The transit network design problem with elastic demand and internalisation of external costs: An application to rail frequency optimisation. Transp Res Part C Emerg Technol 19(6):1276–1305Laporte G, Marín A, Mesa JA, Perea F (2011) Designing robust rapid transit networks with alternative routes. J Adv Transp 45(1):54–65Marín A, García-Ródenas R (2009) Location of infrastructure in urban railway networks. Comput Oper Res 36(5):1461–1477Michaelis M, Schöbel A (2009) Integrating line planning, timetable, and vehicle scheduling: a customer oriented heuristic. Public Transport 1(3):211–232Perea F, Mesa JA, Laporte G (2014) Adding a new station and a road link to a road-rail network in the presence of modal competition. Transp Res Part B Methodol 68:1–16Schmidt M, Schöbel A (2015) The complexity of integrating passenger routing decisions in public transportation models. Networks 65(3):228–243Schmidt ME (2014) Integrating routing decisions in public transportation problems. Springer, New YorkSchöbel A (2012) Line planning in public transportation. OR Spectrum 34:491–510van Oort N, van Nes R (2009) Regularity analysis for optimizing urban transit network design. Public Transport 1(2):155–168Vuchic VR (2005) Urban transit: operations, planning, and economics. Wiley, Hoboken, New Jerse

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in 2 different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early long-term treatment with fingolimod (1 mg/kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in WAG/Rij rats. However, these effects were transitory, as 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control levels. Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced phosphorylated mammalian target of rapamycin and phosphorylated p70S6k levels, and by increased phosphorylated Akt in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic effects of fingolimod. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of lysine 8 of histone H4 (at both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects of fingolimod. However, the antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline

Acceptability of Condom Promotion and Distribution Among 10-19 Year-Old Adolescents in Mpwapwa and Mbeya Rural Districts, Tanzania.

\ud The HIV/AIDS pandemic remains a leading challenge for global health. Although condoms are acknowledged for their key role on preventing HIV transmission, low and inappropriate use of condoms persists in Tanzania and elsewhere in Africa. This study assesses factors affecting acceptability of condom promotion and distribution among adolescents in Mpwapwa and Mbeya rural districts of Tanzania. Data were collected in 2011 as part of a larger cross-sectional survey on condom use among 10-19 year-olds in Mpwapwa and Mbeya rural districts of Tanzania using a structured questionnaire. Associations between acceptability of condom promotion and distribution and each of the explanatory variables were tested using Chi Square. Multivariate logistic regression model was used to examine independent predictors of the acceptability of condom promotion and distribution using STATA (11) statistical software at 5% significance level. Mean age of the 1,327 adolescent participants (50.5% being males) was 13.5 years (SD = 1.4). Acceptance of condom promotion and distribution was found among 37% (35% in Mpwapwa and 39% in Mbeya rural) of the adolescents. Being sexually active and aged 15-19 was the strongest predictor of the acceptability of condom promotion and distribution (OR = 7.78, 95% CI 4.65-12.99). Others were; not agreeing that a condom is effective in preventing transmissions of STIs including HIV (OR = 0.34, 95% CI 0.20-0.56), being a resident of Mbeya rural district (OR = 1.67, 95% CI 1.28-2.19), feeling comfortable being seen by parents/guardians holding/buying condoms (OR = 2.20, 95% CI 1.40-3.46) and living with a guardian (OR = 1.48, 95% CI 1.08-2.04). Acceptability of condom promotion and distribution among adolescents in Mpwapwa and Mbeya rural is low. Effect of sexual activity on the acceptability of condom promotion and distribution is age-dependent and was the strongest. Feeling comfortable being seen by parents/guardians buying or holding condoms, perceived ability of condoms to offer protection against HIV/AIDS infections, district of residence and living arrangements also offered significant predictive effect. Knowledge of these factors is vital in designing successful and sustainable condom promotion and distribution programs in Tanzania.\u

Potentially inappropriate medication in older participants of the Berlin Aging Study II (BASE-II) - Sex differences and associations with morbidity and medication use

INTRODUCTION: Multimorbidity in advanced age and the need for drug treatment may lead to polypharmacy, while pharmacokinetic and pharmacodynamic changes may increase the risk of adverse drug events (ADEs). OBJECTIVE: The aim of this study was to determine the proportion of subjects using potentially inappropriate medication (PIM) in a cohort of older and predominantly healthy adults in relation to polypharmacy and morbidity. METHODS: Cross-sectional data were available from 1,382 study participants (median age 69 years, IQR 67-71, 51.3% females) of the Berlin Aging Study II (BASE-II). PIM was classified according to the EU(7)-PIM and German PRISCUS (representing a subset of the former) list. Polypharmacy was defined as the concomitant use of at least five drugs. A morbidity index (MI) largely based on the Charlson Index was applied to evaluate the morbidity burden. RESULTS: Overall, 24.1% of the participants were affected by polypharmacy. On average, men used 2 (IQR 1-4) and women 3 drugs (IQR 1-5). According to PRISCUS and EU(7)-PIM, 5.9% and 22.6% of participants received at least one PIM, while use was significantly more prevalent in females (25.5%) compared to males (19.6%) considering EU(7)-PIM (p = 0.01). In addition, morbidity in males receiving PIM according to EU(7)-PIM was higher (median MI 1, IQR 1-3) compared to males without PIM use (median MI 1, IQR 0-2, p<0.001). CONCLUSION: PIM use occurred more frequently in women than in men, while it was associated with higher morbidity in males. As expected, EU(7)-PIM identifies more subjects as PIM users than the PRISCUS list but further studies are needed to investigate the differential impact of both lists on ADEs and outcome. KEY POINTS: We found PIM use to be associated with a higher number of regular medications and with increased morbidity. Additionally, we detected a higher prevalence of PIM use in females compared to males, suggesting that women and people needing intensive drug treatment are patient groups, who are particularly affected by PIM use

New Human Papilloma Virus E2 Transcription Factor Mimics: A Tripyrrole-Peptide Conjugate with Tight and Specific DNA-Recognition

BACKGROUND: Human papillomavirus (HPV) is the main causative agent of cervical cancer, particularly high risk strains such us HPV-16, -18 and -31. The viral encoded E2 protein acts as a transcriptional modulator and exerts a key role in viral DNA replication. Thus, E2 constitutes an attractive target for developing antiviral agents. E2 is a homodimeric protein that interacts with the DNA target through an α-helix of each monomer. However, a peptide corresponding to the DNA recognition helix of HPV-16 E2 binds DNA with lower affinity than its full-length DNA binding domain. Therefore, in an attempt to promote the DNA binding of the isolated peptide, we have designed a conjugate compound of the E2 α-helix peptide and a derivative of the antibiotic distamycin, which involves simultaneous minor- and major-groove interactions. METHODOLOGY/PRINCIPAL FINDINGS: An E2 α-helix peptide-distamycin conjugate was designed and synthesized. It was characterized by NMR and CD spectroscopy, and its DNA binding properties were investigated by CD, DNA melting and gel shift experiments. The coupling of E2 peptide with distamycin does not affect its structural properties. The conjugate improves significantly the affinity of the peptide for specific DNA. In addition, stoichiometric amounts of specific DNA increase meaningfully the helical population of the peptide. The conjugate enhances the DNA binding constant 50-fold, maintaining its specificity. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that peptide-distamycin conjugates are a promising tool to obtain compounds that bind the E2 target DNA-sequences with remarkable affinity and suggest that a bipartite major/minor groove binding scaffold can be a useful approach for therapeutic treatment of HPV infection

A genome-wide assessment of the role of untagged copy number variants in type 1 diabetes.

Genome-wide association studies (GWAS) for type 1 diabetes (T1D) have successfully identified more than 40 independent T1D associated tagging single nucleotide polymorphisms (SNPs). However, owing to technical limitations of copy number variants (CNVs) genotyping assays, the assessment of the role of CNVs has been limited to the subset of these in high linkage disequilibrium with tag SNPs. The contribution of untagged CNVs, often multi-allelic and difficult to genotype using existing assays, to the heritability of T1D remains an open question. To investigate this issue, we designed a custom comparative genetic hybridization array (aCGH) specifically designed to assay untagged CNV loci identified from a variety of sources. To overcome the technical limitations of the case control design for this class of CNVs, we genotyped the Type 1 Diabetes Genetics Consortium (T1DGC) family resource (representing 3,903 transmissions from parents to affected offspring) and used an association testing strategy that does not necessitate obtaining discrete genotypes. Our design targeted 4,309 CNVs, of which 3,410 passed stringent quality control filters. As a positive control, the scan confirmed the known T1D association at the INS locus by direct typing of the 5' variable number of tandem repeat (VNTR) locus. Our results clarify the fact that the disease association is indistinguishable from the two main polymorphic allele classes of the INS VNTR, class I-and class III. We also identified novel technical artifacts resulting into spurious associations at the somatically rearranging loci, T cell receptor, TCRA/TCRD and TCRB, and Immunoglobulin heavy chain, IGH, loci on chromosomes 14q11.2, 7q34 and 14q32.33, respectively. However, our data did not identify novel T1D loci. Our results do not support a major role of untagged CNVs in T1D heritability

A reflection on HIV/AIDS research after 25 years

Dr. Robert C. Gallo provides a personal reflection on the 25 year history of AIDS