Nonhalogenated organic molecules from Laurencia algae

The marine red algae of the genus Laurencia have produced more 700 secondary metabolites and exhibited high molecular diversity and intriguing bioactivity. Since the halogenated structures have been comprehensively reviewed previously, this review, covering up to the end of 2012, mainly focuses on the source, structure elucidation, and bioactivity of nonhalogenated organic molecules from Laurencia spp. as well as the relationship between nonhalogenated and halogenated products. Overall, 173 new or new naturally occurring compounds with 58 skeletons, mainly including sesquiterpenes, diterpenes, triterpenes, and C15-acetogenins, are described.The marine red algae of the genus Laurencia have produced more 700 secondary metabolites and exhibited high molecular diversity and intriguing bioactivity. Since the halogenated structures have been comprehensively reviewed previously, this review, covering up to the end of 2012, mainly focuses on the source, structure elucidation, and bioactivity of nonhalogenated organic molecules from Laurencia spp. as well as the relationship between nonhalogenated and halogenated products. Overall, 173 new or new naturally occurring compounds with 58 skeletons, mainly including sesquiterpenes, diterpenes, triterpenes, and C-15-acetogenins, are described

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Latent Class Trajectory Modeling of 2-Component Disease Activity Score in 28 Joints Identifies Multiple Rheumatoid Arthritis Phenotypes of Response to Biologic Disease-Modifying Antirheumatic Drugs

Objective: To determine whether using a reweighted disease activity score that better reflects joint synovitis, i.e., the 2-component Disease Activity Score in 28 joints (DAS28) (based on swollen joint count and C-reactive protein level), produces more clinically relevant treatment outcome trajectories compared to the standard 4-component DAS28. Methods: Latent class mixed modeling of response to biologic treatment was applied to 2,991 rheumatoid arthritis (RA) patients in whom treatment with a biologic disease-modifying antirheumatic drug was being initiated within the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort, using both 4-component and 2-component DAS28 scores as outcome measures. Patient groups with similar trajectories were compared in terms of pretreatment baseline characteristics (including disability and comorbidities) and follow-up characteristics (including antidrug antibody events, adherence to treatments, and blood drug levels). We compared the trajectories obtained using the 4- and 2-component scores to determine which characteristics were better captured by each. Results: Using the 4-component DAS28, we identified 3 trajectory groups, which is consistent with previous findings. We showed that the 4-component DAS28 captures information relating to depression. Using the 2-component DAS28, 7 trajectory groups were identified; among them, distinct groups of nonresponders had a higher incidence of respiratory comorbidities and a higher proportion of antidrug antibody events. We also identified a group of patients for whom the 2-component DAS28 scores remained relatively low; this group included a high percentage of patients who were nonadherent to treatment. This highlights the utility of both the 4- and 2-component DAS28 for monitoring different components of disease activity. Conclusion: Here we show that the 2-component modified DAS28 defines important biologic and clinical phenotypes associated with treatment outcome in RA and characterizes important underlying response mechanisms to biologic drugs

Latent class trajectory modelling of 2‐components‐DAS28 identifies multiple rheumatoid arthritis phenotypes of response to biologic disease modifying anti‐rheumatic drugs

Objectives: To determine whether using a re‐weighted disease activity score that better reflects joint synovitis, the 2‐component DAS28 (2C‐DAS28), based on 28‐swollen joint count and C‐reactive protein, produces more clinically relevant treatment outcome trajectories compared with the standard 4 component DAS28 (4C‐DAS28). Methods: Latent class mixed modelling (LCMM) of response to biologic treatment was applied to 2,991 patients with RA about to commence bDMARD treatment from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort using both 4C‐DAS28 and 2C‐DAS28 as outcomes. Identified patient groups with similar trajectories were compared in terms of pre‐treatment baseline characteristics – including disability, comorbidities ‐ and follow‐up characteristics – including anti‐drug antibody (ADAb) events, adherence to treatments and blood drug levels, We compared the trajectories obtained using the 4C and 2C scores to determine which characteristics were better captured by the 2CDAS28 compared with the 4C‐DAS28 trajectories. Results: Using the 4C‐DAS28 we identified 3 trajectory groups, which is consistent with previous reports. We show that the 4C‐DAS28 captures information relating to depression. Using the 2C‐DAS28, 7 trajectory groups were identified; among them, distinct groups of non‐responders had a higher incidence of respiratory comorbidities and a higher proportion of ADAb events. We also identified a group of participants for which the 2C‐DAS28 disease activity score remained relatively low and which was enriched for patients who were non‐adherent to treatment. This highlights the utility of both the 4C and 2C‐DAS28 for monitoring different components of disease activity. Conclusions: Here we show that the 2C‐DAS28 modified disease activity score defines important biological and clinical phenotypes associated with treatment outcome in RA and characterizes important underlying response mechanisms to biologic drugs

Long-term exposure to intranasal oxytocin in a mouse autism model

Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse's chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT

Use of Antiretrovirals for HIV Prevention: What Do We Know and What Don’t We Know?

Pre-exposure prophylaxis (PrEP), in which HIV uninfected persons with ongoing HIV risk use antiretroviral medications as chemoprophylaxis against sexual HIV acquisition, is a promising new HIV prevention strategy. Proof-of-concept that PrEP, as oral or vaginal topical tenofovir-based products, protects against sexual HIV acquisition has been demonstrated in clinical trials conducted among men who have sex with men and heterosexual men and women. The degree of HIV protection in these trials was strongly related to the level of adherence to PrEP. Many questions are yet unanswered – including how to motivate uptake of and sustain adherence to PrEP for HIV prevention, how much PrEP use is enough to achieve HIV protection, and the potential of “next-generation” PrEP agents to improve on this effective technology