Genetic Architecture of Circulating Very-Long-Chain (C24:0 and C22:0) Ceramide Concentrations

OBJECTIVE: Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations.METHODS: Heritability and genome-wide association studies of plasma C24:0 and C22:0 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment.RESULTS: The multivariable-adjusted heritability for C22:0 and C24:0 ceramides was 0.42 (standard error [SE], 0.07; p=1.8E-9) and 0.25 (SE, 0.08; p=0.00025), respectively. Nineteen single nucleotide polymorphisms (SNPs), all on chromosome 20, significantly associated with C22:0 concentrations; the closest gene to these variants was SPTLC3. The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (p=2.83E-11). Nine SNPs, all on chromosome 20 and close to SPTLC3, were significantly associated with C24:0 ceramide concentrations. All 9 were also significantly related to plasma C22:0 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C24:0 ceramide concentrations (p=9.94E-09).CONCLUSION: SNPs near the SPTLC3 gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of de novo sphingolipid synthesis) were associated with plasma C22:0 and C24:0 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C24:0 and C22:0 ceramide modulation.

Maintaining Reduced Noise Levels in a Resource-Constrained Neonatal Intensive Care Unit by Operant Conditioning.

Objective: To evaluate the efficacy of operant conditioning in sustaining reduced noise levels in the neonatal intensive care unit (NICU) Design: Quasi-experimental study on quality of care. Setting: Level III NICU of a teaching hospital in south India. Participants: 26 staff employed in the NICU. (7 Doctors, 13 Nursing staff and 6 Nursing assistants). Intervention: Operant conditioning of staff activity for 6 months. This method involves positive and negative reinforcement to condition the staff to modify noise generating activities. Main outcome measures: Comparing noise levels in decibel: A weighted [dB (A)] before conditioning with levels at 18 and 24 months after conditioning. Decibel: A weighted accounts for noise that is audible to human ears. Results: Operant conditioning for 6 months sustains the reduced noise levels to within 62 dB (A) in ventilator room (95% CI: 60.4 – 62.2) and isolation room (95% CI: 55.8 – 61.5). In the pre-term room, noise can be maintained within 52 dB (A) (95 % CI: 50.8 – 52.6). This effect is statistically significant in all the rooms at 18 months (P = 0.001). At 24 months post conditioning there is a significant rebound of noise levels by 8.6, 6.7 and 9.9 dB (A) in the ventilator, isolation and pre-term room, respectively (P=0.001). Conclusion: Operant conditioning for 6 months was effective in sustaining reduced noise levels. At 18 months post conditioning, the noise levels were maintained within 62 dB (A), 60 dB (A) and 52 dB (A) in the ventilator, isolation and pre-term room, respectively. Conditioning needs to be repeated at 12 months in the ventilator room and at 18 months in the other rooms.

An update on osteoarthritis

É feita uma atualizaçao sobre osteoartrite (OA), a desordem reumatológica mais comum e causa importante da morbidade e incapacidade crônica. Sao revistos epidemiologia, classificaçao, patogenia, genética e tratamento. É salientado o papel dos processos enzimáticos, ao lado dos fatores mecânicos, na degradaçao da matriz cartilaginosa osteartrítica. Os condrócitos sao considerados a maior fonte de enzimas degradadoras. As enzimas envolvidas no catabolismo da matriz cartilaginosa osteoartrítica incluem as metaloproteases (colagenase, estromelisina e gelatinase), serina-proteases e tiol-proteases. A atividade biológica das metaloproteases é controlada por ativadores e inibidores, como TIMP-1 (tissue inhibitor of metallo-protease), sintetizado pelos condrócitos e deficiente na cartilagem OA, permitindo o aumento da atividade das metaloproteases. Outros fatores que podem estar envolvidos na patogenia da OA sao as citocinas, que modulam o metabolismo do tecido conjuntivo. As principais citocinas que se acredita estarem envolvidas na OA sao IL-1, IL-6 e TNF. IL-1 e TNF-alfa podem aumentar a síntese da metaloproteases e determinar o aumento da síntese de prostaglandinas pela células sinoviais e podem ser responsáveis por algum dos mecanismos patogênicos na OA. Estudos de genética molecular identificaram colágenos mutantes do tipo II como causa específica de insuficiência da matriz cartilaginosa em três geraçoes de uma família de nao consanguíneos com OA de início prematuro associada a condrodisplasia. Outras formas de OA mostraram predisposiçao genética, principalmente a OA generalizada nodal, associada com o aumento de frequência de HLA-A1, B8. O manuseio atual da OA é principalmente sintomático e de sustentaçao. Quando e como usar os antiinflamatórios nao esteróides (NSAIDS) mais eficientemente necessita mais estudos. Dados de experiências in vitro e in vivo relativos ao efeito dos NSAIDS sobre a cartilagem precisam ser interpretados com precauçao. Vários avanços na patogenia e tratamento da OA ocorreram na última década. O conceito de OA como processo de uso e desgastante, conquanto parcialmente sustentado, tem sido suplementado com a noçao de que certas influências genéticas e bioquímicas podem também desempenhar papel primário no desenvolvimento da OA