Permanent cardiac pacing for severe pallid breath-holding spells

We report the case of an infant affected by frequent episodes of loss of consciousness with the clinical features of pallid breath-holding attacks. Prolonged asystole, up to 26 seconds, was demonstrated by Holter monitoring. The patient was treated with permanent pacemaker implantation, followed by complete symptom resolution during a 26-month follow-up.     

An overview of the patterns of prescription opioid use,costs and related harms in Australia

AimsTo report Australian population trends in subsidized prescribed opioid use, total costs to the Australian government to subsidize these medicines and opioid-related harms based on hospitalizations and accidental poisoning deaths.MethodsWe utilized three national aggregated data sources including dispensing claims from the Pharmaceutical Benefits Scheme, opioid-related hospitalizations from the National Hospital Morbidity Database and accidental poisoning deaths from the Australian Bureau of Statistics.ResultsBetween 1992 and 2012, opioid dispensing episodes increased 15-fold (500 000 to 7.5 million) and the corresponding cost to the Australian government increased 32-fold ($8.5 million to $271 million). Opioid-related harms also increased. Opioid-related hospitalizations increased from 605 to 1464 cases (1998–2009), outnumbering hospitalizations due to heroin poisonings since 2001. Deaths due to accidental poisoning (pharmaceutical opioids and illicit substances combined) increased from 151 to 266 (2002–2011), resulting in a rise in the death rate of 0.78 to 1.19 deaths/100 000 population over 10 years. Death rates increased 1.8 fold in males and 1.4 fold in females.ConclusionsThe striking increase in opioid use and related harms in Australia is consistent with trends observed in other jurisdictions. Further, there is no evidence to suggest these increases are plateauing. There is currently limited evidence in Australia about individual patterns of opioid use and the associated risk of adverse events. Further research should focus on these important issues so as to provide important evidence supporting effective change in policy and practice.     

Pharmacological Stimulation of the Brain Serotonin Receptor 7 as a Novel Therapeutic Approach for Rett Syndrome

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG-binding protein 2 gene (MECP2) cause >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2–308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability.     

The HIV 5′ Gag Region Displays a Specific Nucleotide Bias Regulating Viral Splicing and Infectivity

Alternative splicing and the expression of intron-containing mRNAs is one hallmark of HIV gene expression. To facilitate the otherwise hampered nuclear export of non-fully processed mRNAs, HIV encodes the Rev protein, which recognizes its intronic response element and fuels the HIV RNAs into the CRM-1-dependent nuclear protein export pathway. Both alternative splicing and Rev-dependency are regulated by the primary HIV RNA sequence. Here, we show that these processes are extremely sensitive to sequence alterations in the 5’coding region of the HIV genomic RNA. Increasing the GC content by insertion of either GFP or silent mutations activates a cryptic splice donor site in gag, entirely deregulates the viral splicing pattern, and lowers infectivity. Interestingly, an adaptation of the inserted GFP sequence toward an HIV-like nucleotide bias reversed these phenotypes completely. Of note, the adaptation yielded completely different primary sequences although encoding the same amino acids. Thus, the phenotypes solely depend on the nucleotide composition of the two GFP versions. This is a strong indication of an HIV-specific mRNP code in the 5′ gag region wherein the primary RNA sequence bias creates motifs for RNA-binding proteins and controls the fate of the HIV-RNA in terms of viral gene expression and infectivity.     

In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets

Although the prognosis of pediatric leukemias has improved considerably, many patients still have relapses. Tipifarnib, a farnesyl transferase inhibitor (FTI), was developed to target malignancies with activated RAS, including leukemia. We tested 52 pediatric acute myeloid leukemia (AML) and 36 pediatric acute lymphoblastic leukemia (ALL) samples for in vitro sensitivity to tipifarnib using a total cell-kill assay and compared these results to those obtained with normal bone marrow (N BM) samples (n = 25). AML samples were significantly more sensitive to tipifarnib compared to B-cell precursor ALL (BCP ALL) or N BM samples. Within AML, French-American-British (FAB) M5 samples were most sensitive to tipifarnib. T-cell ALL samples were significantly more sensitive than BCP ALL and N BM samples. In AML there was a marked correlation between tipifarnib resistance and daunorubicin or etoposide resistance, but not to cytarabine or 6-thioguanine. RAS mutations were present in 32% of AML and 18% of ALL samples, but there was no correlation between RAS mutational status and sensitivity to tipifarnib. Future studies are needed to identify biomarkers predictive of tipifarnib sensitivity. In addition, clinical studies, especially in T-cell ALL, seem warranted.     

Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials

Increased body weight is a strong risk factor for hypertension. A meta-analysis of randomized controlled trials was performed to estimate the effect of weight reduction on blood pressure overall and in population subgroups. Twenty-five randomized, controlled trials (comprising 34 strata) published between 1966 and 2002 with a total of 4874 participants were included. A random-effects model was used to account for heterogeneity among trials. A net weight reduction of -5.1 kg (95% confidence interval [CI], -6.03 to -4.25) by means of energy restriction, increased physical activity, or both reduced systolic blood pressure by -4.44 mm Hg (95% CI, -5.93 to -2.95) and diastolic blood pressure by -3.57 mm Hg (95% CI, -4.88 to -2.25). Blood pressure reductions were -1.05 mm Hg (95% CI, -1.43 to -0.66) systolic and -0.92 mm Hg (95% CI, -1.28 to -0.55) diastolic when expressed per kilogram of weight loss. As expected, significantly larger blood pressure reductions were observed in populations with an average weight loss >5 kg than in populations with less weight loss, both for systolic (-6.63 mm Hg [95% CI, -8.43 to -4.82] vs -2.70 mm Hg [95% CI, -4.59 to -0.81]) and diastolic (-5.12 mm Hg [95% CI, -6.48 to -3.75] vs -2.01 mm Hg [95% CI, -3.47 to -0.54]) blood pressure. The effect on diastolic blood pressure was significantly larger in populations taking antihypertensive drugs than in untreated populations (-5.31 mm Hg [95% CI, -6.64 to -3.99] vs -2.91 mm Hg [95% CI, -3.66 to -2.16]). This meta-analysis clearly shows that weight loss is important for the prevention and treatment of hypertension.     

Trends in health expectancy indicators in the older adult population in Belgium between 1997 and 2004

The objective is to assess if longer life in Belgium is associated with more healthy years through the evaluation of trends (1997–2004) in health expectancy indicators at ages 65 and 80 covering different health domains: self-perceived health, chronic morbidity, disease clusters, and disability. Information was obtained from Belgian Health Interview Surveys. Health expectancies were calculated using the Sullivan method. Among males at age 65, the increase in years expected to live without chronic morbidity, without a disease cluster or without disability exceeded the increase of the life expectancy (LE). The rise in LE in good self-perceived health was equal to the gain in LE. Among women at age 65 and among men and women at age 80, none of the changes in the expected years of life in good health in any health domain were statistically significant. At age 65 among women, the increase in LE was smaller than the increase in years without chronic disease or without disability. The increase in years without disease clusters was less that the LE increase. At age 80 among men, the years without disability increased as the LE, with a shift toward years with moderate limitations. In any other health domains for men (except co-morbidity) and in all domains for women the years in good health either decreased or increased less than the LE. The recent rise in life expectancy in Belgium is, among the youngest old and especially among males, accompanied by an improved health status. At age 80 and particularly among women expansion of unhealthy years prevails.