Treatment of Paget's disease of bone with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate

Summary 4-amino-1-hydroxybutylidene-1,1-bis-phosphonate (AHButBP) was given intravenously (2.5–25 mg/day for 4 days) to 14 patients with Paget's disease of bone, five of whom had been treated with dichloromethylidene bisphosphonate (Cl₂MBP) 32 months earlier. In the nine patients who had not been treated previously with bisphosphonates, the short course of AHButBP induced a suppression of serum alkaline phosphatase and urinary hydroxyproline values down to 30% of initial values. The biochemical suppression of the disease was sustained for 2–18 months and the time to relapse did correlate to the logarithm of the dose (P<0.001). In the five patients previously treated for Paget's disease, an apparent resistence to treatment with AHButBP was observed. However, in these patients both serum alkaline phosphatase and urinary hydroxyproline fell to or even below the nadir values which had previously been achieved with Cl₂MBP, irrespective of the degree of relapse. Thus the degree of suppression of Paget's disease of bone, achievable after treatment with bisphosphonates, seems to be constant for each patient, such that normal levels of serum alkaline phosphatase and urinary hydroxyproline cannot usually be attained in patients with extremely active disease.     

Telomerase activity,telomere length and hTERT DNA methylation in peripheral blood mononuclear cells from monozygotic twins with discordant smoking habits

Increased telomerase expression has been implicated in the pathogenesis of lung cancer and, since the primary cause of lung cancer is smoking, an association between telomerase reactivation and tobacco smoke has been proposed. In this work an investigation has been performed to assess the relationship between tobacco smoke exposure and telomerase activity (TA) in peripheral blood mononuclear cells of healthy smokers. The methylation status of the catalytic subunit of telomerase hTERT was concurrently investigated to assess the possible association between epigenetic modifications of hTERT and TA. Besides, the association between smoke and telomere length (TL) has been evaluated. Healthy monozygotic twins with discordant smoking habits were selected as study population to minimize inter‐individual differences because of demographic characteristics and genetic heterogeneity. Statistically significant higher values of TA and TL were observed in smokers compared to nonsmoker co‐twins. The multivariate analysis of data showed, besides smoking habits (P = 0.02), an influence of gender (P = 0.006) and BMI (P = 0.001) on TA and a borderline effect of gender (P = 0.05) on TL. DNA methylation analysis, focused on 100 CpG sites mapping in hTERT, highlighted nine CpG sites differentially methylated in smokers. When co‐twins were contrasted, selecting as variables the intra‐twin difference in TA and hTERT DNA methylation, a statistically significant inverse correlation (P = 0.003) was observed between TA and DNA methylation at the cg05521538 site. In conclusion, these results indicate an association of tobacco smoke with TA and TL and suggest a possible association between smoke‐induced epigenetic effects and TA in healthy smokers. Environ. Mol. Mutagen. 58:551–559, 2017. © 2017 Wiley Periodicals, Inc.     

Interpretation of liver chemistries in adult donors after living donor liver transplantation

OBJECTIVES: The safety of donors is paramount in adult living donor liver transplantation. Our goal is to compare the pattern of recovery of hepatic synthetic function and aminotransferases in healthy adult donors with and without complications. METHODS: We reviewed 47 consecutive patients undergoing right donor hepatectomy at our center. Laboratory data were collected through the first 2 postoperative weeks and results from donors with and without complications were compared. RESULTS: Donor morbidity was 25% and there were no donor deaths. Total bilirubin peaked on postoperative day 3, whereas aminotransferases and international normalized ratio peaked on postoperative day 1. Peak total bilirubin was higher in patients with fluid collections (n = 7) compared with those without fluid collections (n = 40), 4.6 mg/dL and 2.3 mg/dL, respectively, P = 0.02. On postoperative day 3 the peak total bilirubin was greater than 3.0 mg/dL in 86% of donors with fluid collections and 15% of donors without fluid collections, (P = 0.0005) whereas aminotransferases and alkaline phosphatase were not significantly different between these 2 groups. CONCLUSIONS: After right donor hepatectomy a total bilirubin greater than 3.0 mg/dL on postoperative day 3 should prompt an evaluation for a fluid collection, even if other liver tests are normal or declining.     

The Benefits of Hypothermic Machine Perfusion Are Enhanced With Vasosol and α-Tocopherol in Rodent Donation After Cardiac Death Livers

The use of hypothermic machine perfusion (HMP) has recently been used to show an improvement in both standard and extended criteria donor liver grafts but creating a more dynamic preservation environment that can be supplemented with a variety of additives to aid in cold temperature metabolism and vasodilatation. Increasing the benefits of HMP, we explore the use of α-tocopherol in reducing inflammatory markers and apoptotic pathways to reduce the incidence of preservation injury. We explored the use of a donation after cardiac death (DCD) rodent model to test the additive benefits of α-tocopherol in HMP. The addition of α-tocopherol reduced the level of alanine aminotransferase (ALT) over the course of reperfusion as well, reduced the levels of inflammatory cytokines within a 90 minute reperfusion biopsy. Further benefit was seen with α-tocopherol through the reduction of the level of caspase 3/7 in the circulation, shown to be a result of the reduction of the levels of Cytochrome C mRNA. Liver perfusion with Vasosol® and HMP could benefit further from the addition of α-tocopherol to existing formulations of Vasosol®.     

Healthy Aging and Dietary Patterns

A number of factors contribute to the complex process of aging, which finally define whether someone will or not develop age-associated chronic diseases in late life. These determinants comprise genetic susceptibility as well as various behavioral, environmental, and dietary factors, all of which have been shown to influence specific pathways regulating the aging process and the extension of life, which makes longevity a multidimensional phenomenon. Although a “miraculous elixir” or a “nutrition pill” are not plausible, researchers agree on the notion that nutritional factors have major impact on the risk of age-associated chronic non-communicable diseases and mortality. In recent years nutrition research in relation to health outcomes has considerably changed from focusing exclusively on single nutrients to considering combinations of foods rather than nutrients in isolation. Although research on specific nutrients is scientifically valid providing crucial evidence on the mechanisms by which nutrition impacts health, the recent switch targeting the multifaceted synergistic interplay among nutrients, other dietary constituents, and whole foods, has promoted emerging interest on the actions of total dietary patterns. This narrative review aims to describe some specific dietary patterns with evidence of associations with reduction in the incidence of chronic diseases allowing older adults to live a long-lasting and healthier life, and confirming the powerful impact nutrition can exert on healthy aging.     

Pulsatile machine perfusion with Vasosol solution improves early graft function after cadaveric renal transplantation

BACKGROUND: Cold storage is the most common method of preservation in renal transplantation, but pulsatile machine perfusion (MP) is increasingly used for purposes of ex vivo assessment and resuscitation of high risk allografts. Vasosol (VSL) MP solution (MPS) (Pike Laboratories Inc, Eagle, PA) is a novel perfusate with enhanced vasodilatory and antioxidant capacity. We report our experience with VSL in machine preservation of renal allografts. METHODS: Locally procured cadaver kidney pairs undergoing MP were randomized to VSL or control solution (Belzer MPS; Trans-Med, Elk River, MN). En bloc perfusion was performed according to standard MP procedures. Transplantation was performed at 1 of 12 local transplant centers. Donor and recipient data were collected prospectively. RESULTS: Data from 162 transplanted kidneys were analyzed. A total of 82 renal grafts were perfused with VSL, and 80 were perfused with control solution. No organs were lost secondary to the technique of MP. There was no difference in donor or recipient age between groups. Kidneys perfused with VSL exhibited significantly higher rates of immediate function and significantly less delayed graft function (12.2% vs. 21.2%). Discharge creatinine and length of stay were also significantly improved in the VSL group. One-year graft and patient survivals were equivalent (95%) in both groups. CONCLUSIONS: VSL improved early graft function and shortened the length of stay compared with Belzer MPS. Further improvement in preservation solutions in conjunction with pulsatile perfusion shows promise in improving early outcomes after renal transplantation, especially for extended criteria donor kidneys.     

Combination of DNA repair gene single nucleotide polymorphisms and increased levels of DNA adducts in a population-based study.

Inherited single nucleotide polymorphisms (SNPs) of DNA repair genes may contribute to variations in DNA repair capacity and susceptibility to cancer. We investigated the role of SNPs in three DNA repair genes (X-ray repair cross-complementing group 1-Arg399Gln, exon 10; X-ray repair cross-complementing group 3-Thr241Met, exon 7; and xeroderma pigmentosum-D-Lys751Gln, exon 23) and their combination, in modulating the levels of "bulky" DNA adducts in a population sample of 628 Italian healthy individuals belonging to the prospective European project "European Prospective Investigation into Cancer and Nutrition." DNA-adduct levels were measured as relative adduct level per 10(9) nucleotides by (32)P-post DNA labeling assay in WBCs from peripheral blood. Genotyping was performed by PCR-RFLP analysis or primer extension/denaturing high-performance liquid chromatography technique. We found a dose-response relationship between the number of at-risk alleles and levels of adducts (P = 0.0046). Individuals with at least three variant alleles had a statistically significant odds ratio (OR) for being in the highest tertile of adducts compared with those with undetectable adducts [three alleles, adjusted OR = 5.07, 95% confidence interval (CI) = 1.29-19.9; four alleles, adjusted OR = 5.03, 95% CI = 1.18-21.45; five alleles, adjusted OR = 7.65, 95% CI = 0.94-62.2]. Our study suggests that the combined effect of multiple variant alleles may be more important than the investigation of single SNP in modulating DNA repair capacity.     

Association study of the I/D polymorphism and plasma angiotensin-converting enzyme (ACE) as risk factors for stent restenosis

The ID (insertion/deletion) polymorphism of the ACE (angiotensin-converting enzyme) gene controls plasma ACE levels. Both have been correlated with ISR (in-stent restenosis) in preliminary analyses, but not confirmed in larger studies. In the present study, baseline and 6-month quantitative coronary analysis were performed in 897 patients who had stent implantation and the ID polymorphism genotyped. Plasma ACE levels were measured in 848 patients (95%). Restenosis rates among genotypes were 31.2% DD, 25.5% ID and 28.8% II (not significant). Plasma ACE levels were significantly higher in restenotic patients compared with patients without restenosis (30.7+/-18.6 units/l compared with 22.8+/-12.8 units/l; P=0.0001) and a strong independent predictor of ISR [OR (odds ratio)=3.70; 95% CI (confidence interval), 2.40-5.71; P<0.0001], except in diabetics. In the subgroup of diabetics and patients with AMI (acute myocardial infarction), the DD genotypes actually had a lower risk of ISR than the II genotypes (diabetics, OR=0.16; 95% CI, 0.04-0.69; P=0.014; and patients with AMI, OR=0.21; 95% CI, 0.061-0.749; P=0.016). After exclusion of diabetics and patients with AMI, ISR rates for genotypes in 632 patients were 31.7% DD, 24.3% ID and 17.6% II (P=0.02; DD compared with non-DD OR=1.57; 95% CI, 1.09-2.25). The association between the D allele and ISR observed in selected populations does not hold with a larger sample size. Other than sample size, clinical variables can modulate the association between ID polymorphism and ISR. Plasma ACE level is a risk factor for ISR, independently of the ID genotype.     

Flushing in rosacea: An experimental approach

Summary A simple method is described which causes rosacea patients to flush. This flush is experienced similarly to the flush which occurs spontaneously and its intensity can be measured and monitored wuantitatively. Therefore, it can be used as a suitable experimental tool to measure and compare the inhibitory effects of some drugs, as well as the fluctuations of the blood level of certain chemical vasoactive mediators.     

Distinguishing androgenetic alopecia from chronic telogen effluvium when associated in the same patient: a simple noninvasive method

BACKGROUND: Distinguishing chronic telogen effluvium (CTE) from androgenetic alopecia (AGA) may be difficult especially when associated in the same patient. OBSERVATIONS: One hundred consecutive patients with hair loss who were clinically diagnosed as having CTE, AGA, AGA + CTE, or remitting CTE. Patients washed their hair in the sink in a standardized way. All shed hairs were counted and divided "blindly" into 5 cm or longer, intermediate length (>3 to <5 cm), and 3 cm or shorter. The latter were considered telogen vellus hairs, and patients having at least 10% of them were classified as having AGA. We assumed that patients shedding 200 hairs or more had CTE. The kappa statistic revealed, however, that the best concordance between clinical and numerical diagnosis (kappa = 0.527) was obtained by setting the cutoff shedding value at 100 hairs or more. Of the 100 patients, 18 with 10% or more of hairs that were 3 cm or shorter and who shed fewer than 100 hairs were diagnosed as having AGA; 34 with fewer than 10% of hairs that were 3 cm or shorter and who shed at least 100 hairs were diagnosed as having CTE; 34 with 10% or more of hairs that were 3 cm or shorter and who shed at least 100 hairs were diagnosed as having AGA + CTE; and 14 with fewer than 10% of hairs that were 3 cm or shorter and who shed fewer than 100 hairs were diagnosed as having CTE in remission. CONCLUSION: This method is simple, noninvasive, and suitable for office evaluation.