Age-Dependent Progression in Lung Pathophysiology can be Prevented by Restoring Fatty Acid and Ceramide Imbalance in Cystic Fibrosis

Purpose

Cystic fibrosis (CF) is a progressive disease which causes a continuous decline in lung capacity with age. Our study aimed to investigate the age-dependent deterioration in lung function and the effects of treatment with Fenretinide formulation (LAU-7b) in Cftr knockout (KO) mice.

Methods

Non-invasive whole-body plethysmography (WBP) was done to measure the baseline lung functions of KO and wild-type (WT) mice at the ages of 2 and 4 months. Mice were then treated for 21 days with PBS or 10 mg/kg/day LAU-7b initiated at 4 and 7 months. Standard airway resistance measurements, haematoxylin and eosin staining, and analysis of lipids, and markers of oxidation were performed.

Results

The 4- and 7-month-old KO mice had significantly higher lung enhanced pause (Penh) and resistance values than age-matched WT mice and 2-month-old KO mice. Likewise, analysis of ceramides showed that PBS-treated mice had higher levels of long-chain ceramides (LCCs; C14-C18) and lower levels of very-long-chain ceramides (VLCCs; C24-C26) compared to LAU-7b-treated mice. Cftr KO mice displayed markedly greater inflammatory cell infiltration and epithelial hyperplasia at the ages of 2, 4, and 7 months compared to WT. LAU-7b treatment significantly diminished this cellular infiltration and epithelial hyperplasia compared to PBS-treated mice.

Conclusion

Our results demonstrate a progressive age-dependent decline in lung function in Cftr KO mice. Treatment with LAU-7b corrects the lipid imbalance observed in the aging KO and WT mice and, more importantly, inhibits the age-dependent deterioration in lung physiology and histopathology.

     

Early changes in parathyroid hormone concentrations in HIV-infected patients initiating antiretroviral therapy with tenofovir

Initiation of combined antiretroviral therapy (cART) is associated with bone loss, which may be more intense with regimens including tenofovir. The underlying mechanisms are not well understood. Cross-sectional data have linked tenofovir with higher parathyroid hormone (PTH) concentrations in patients with vitamin D deficiency. We performed a longitudinal study with a 48-week follow-up to evaluate sequential changes in PTH and 25-hydroxyvitamin D [25(OH)D] levels in patients starting cART with either tenofovir/emtricitabine or abacavir/lamivudine. Fifty-seven patients were included, 31 initiating tenofovir/emtricitabine and 26 initiating abacavir/lamivudine. Median PTH levels turned out to be significantly higher among tenofovir/emtricitabine users at week 4 (p=0.01), week 24 (p=0.008), and week 36 (p=0.02), and were above the upper limits of normal values (ULN) at weeks 24, 36, and 48 only in patients receiving tenofovir/emtricitabine. 25(OH)D, serum and urine calcium and phosphate, and renal-tubular maximum reabsorption of phosphate to the glomerular filtration rate (TmP/GFR) levels did not differ between the two treatment arms over the study period. Among tenofovir/emtricitabine users, median (interquartile range) PTH concentrations were significantly higher in patients with suboptimal 25(OH)D levels (<30 μg/liter) at week 24 [63 (57.8-82.4) ng/liter vs. 54.3 (34.4-63.067.5) ng/liter, p=0.05] and week 48 [67.5 (59.6-86.0) ng/liter vs. 41.9 (37.3-68.8) ng/liter, p=0.03]. A multivariable logistic regression model showed that tenofovir/emtricitabine use was an independent predictor of high PTH levels (≥53 ng/liter). Starting cART with tenofovir regimens is associated with an elevation in PTH plasma concentrations soon after introducing the drug. Suboptimal baseline 25(OH)D levels increase the risk of developing secondary hyperparathyroidism among tenofovir users.     

Antithrombotic treatment tailoring and risk score evaluation in elderly patients diagnosed with an acute coronary syndrome

Age is an important prognostic factor in the outcome of acute coronary syndromes (ACS). A substantial percentage of patients who experience ACS is more than 75 years old, and they represent the fastest-growing segment of the population treated in this setting. These patients present different patterns of responses to pharmacotherapy, namely, a higher ischemic and bleeding risk than do patients under 75 years of age. Our aim was to identify whether the currently available ACS ischemic and bleeding risk scores, which has been validated for the general population, may also apply to the elderly population. The second aim was to determine whether the elderly benefit more from a specific pharmacological regimen, keeping in mind the numerous molecules of antiplatelet and antithrombotic drugs, all validated in the general population. We concluded that the GRACE (Global Registry of Acute Coronary Events) risk score has been extensively validated in the elderly. However, the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) bleeding score has a moderate correlation with outcomes in the elderly. Until now, there have not been head-to-head scores that quantify the ischemic versus hemorrhagic risk or scores that use the same end point and timeline (e.g., ischemic death rate versus bleeding death rate at one month). We also recommend that the frailty score be considered or integrated into the current existing scores to better quantify the overall patient risk. With regard to medical treatment, based on the subgroup analysis, we identified the drugs that have the least adverse effects in the elderly while maintaining optimal efficacy.     

Child Sexual Abuse and Sexual Revictimization

Research identifying rates and effects of adult/adolescent sexual revictimization among child sexual abuse victims was reviewed. Approximately one-third of child sexual abuse victims report experiencing repeated victimization. Child sexual abuse victims have a 2 to 3 times greater risk of adult revictimization than women without a history of child sexual abuse. Physical contact in abuse and revictimization in adolescence were found to lead to the greatest risk of revictimization. Repeated victims had more symptoms of Post Traumatic Stress Disorder (PTSD) and dissociation than women with a history of child sexual abuse alone. Theories of revictimization and mediating variables were also reviewed. Clearer definitions of repeated victimization are needed and future research should include studies that follow child sexual abuse victims prospectively.     

Oxidative stress induced in <Emphasis Type="Italic">Hyalella azteca</Emphasis> by an effluent from a NSAID-manufacturing plant in Mexico

Production in the pharmaceutical industry has increased and along with it, the amount of wastewater of various characteristics and contaminant concentrations. The main chemicals in these effluents are solvents, detergents, disinfectants—such as sodium hypochlorite (NaClO)—and pharmaceutical products, all of which are potentially ecotoxic. Therefore, this study aimed to evaluate the oxidative stress induced in the amphipod Hyalella azteca by the effluent from a nonsteroidal anti-inflammatory drug (NSAID)-manufacturing plant. The median lethal concentration (72 h-LC₅₀) was determined and H. azteca were exposed to the lowest observed adverse effect level (0.0732 %) for 12, 24, 48 and 72 h, and biomarkers of oxidative stress were evaluated [hydroperoxide content (HPC), lipid peroxidation (LPX), protein carbonyl content (PCC), and the activity of the superoxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)]. Statistically significant increases with respect to the control group (P < 0.05) were observed in HPC, LPX and PCC in H. azteca at all exposure times. Antioxidant enzymes activity SOD, CAT and GPx activity also increased significantly (P < 0.05) with respect to the control group. In conclusion, the industrial effluent analyzed in the present study contains NSAIDs and NaClO, and induces oxidative stress in H. azteca.     

Mutations in TBX1 genocopy the 22q11.2 deletion and duplication syndromes: a new susceptibility factor for mental retardation

A screen for TBX1 gene mutations identified two mutations in patients with some features compatible with the 22q11.2-deletion syndrome but with no deletions. One is a de novo missense mutation and the other is a 5' untranslated region (5'UTR) C>T change that affects a nucleotide with a remarkable trans-species conservation. Computer modelling shows that the 5'UTR change is likely to affect the mRNA structure and in vitro translation experiments demonstrate that it produces a twofold increase in translation efficiency. Recently, duplications in the 22q11.2 region were reported in patients referred for fragile-X determination because of cognitive and behavioural problems. Because the 5'UTR nucleotide change may be a functional equivalent of a duplication of the TBX1 gene, we decided to screen 200 patients who had been referred for fragile-X determination and 400 healthy control individuals. As a result, we found the 5'UTR mutation to be present in three patients with mental retardation or behavioural problems and absent in control individuals of the same ethnic background. This observation suggests that it may be reasonable to screen for such mutation among patients with unspecific cognitive deficits and we provide an easy and quick way to do it with an amplification refractory mutation system (ARMS) approach. To our knowledge, this is the first human mutation showing that TBX1 is a candidate causing mental retardation associated with the 22q11.2 duplication syndrome.