Slow injection of prostaglandin E1 decreases associated penile pain

Objectives

A randomized, double-blind study to determine whether speed of intracavernous injection of prostaglandin E, (PGE,) is associated with pain.

Methods

On two separate occasions, using two different speeds of injection (5 versus 60 seconds), 11 subjects received the same dose of PGE, that they used at home. The presence, duration, and intensity of pain were recorded.

Results

We found that fast penile injection of PGE, was associated with a greater intensity of pain (P = 0.04).

Conclusions

Slow injection of PGE, is less often associated with penile pain, the most common adverse effect of this treatment.     

DNA adducts and combinations of multiple lung cancer at‐risk alleles in environmentally exposed and smoking subjects

Interindividual variation in DNA adduct levels in individuals exposed to similar amounts of environmental carcinogens may be due to genetic variability. We analysed the influence of genes involved in determining/modifying DNA damage, including microsomal epoxide hydrolase1 (EPHX1) His139Arg, N‐acetyl‐transferase, NAD(P)H:quinone oxidoreductase1 (NQO1) Pro187Ser, manganese superoxide dismutase2 (MnSOD2) Val16Ala, and apurinic/apyrimidinic endonuclease1 (APE1) Asp148Glu polymorphisms in blood of 120 smokers. Subsequently, we examined the effects of the combinations of the variant alleles of EPHX, NQO1 and MnSOD2 together with the wild type allele of APE1 on DNA damage by calculating the “sum of at‐risk alleles.” We reviewed the studies examining the relationships of DNA adducts with at‐risk alleles in environmentally exposed subjects. Our findings showed that smokers carrying the EPHX1–139Arg and the NQO1–187Ser variants were significantly more likely to have higher adduct levels. Null associations were found with the other variants. Nevertheless, DNA adduct levels in smokers with ≥5 at‐risk alleles were significantly different from those with fewer than two alleles. A similar picture emerged from studies of DNA adducts and at‐risk alleles in environmentally exposed and smoking subjects. Certain at‐risk allele combinations may confer a greater likelihood of increased levels of adducts after environmental insults. The increase in DNA adduct levels in susceptible subjects exposed to environmental carcinogens may reflect changes in the mechanisms that protect cells from the accumulation of genetic damage. Alterations of the physiological processes designed to maintain homeostasis may reduce the individual “genotoxic tolerance” to environmental challenges and result in phenotypes characterized by high levels of DNA adducts. Environ. Mol. Mutagen. 54:375–383, 2013. © 2013 Wiley Periodicals, Inc.     

Incomplete protection of genetic integrity of mature spermatozoa against oxidative stress

Although DNA damage in human spermatozoa is associated with adverse health effects, its origin is not fully understood. Therefore, we assessed biomarkers in ejaculates that retrospectively reflect processes that occurred in the epididymis or testis. Smoking increased the amount of DNA strand breaks (P < 0.01), and enhanced the presence of vitamin C radicals in seminal plasma. In vitro, vitamin C protected mature spermatozoa against DNA damage, but this protection appeared to be insufficient in vivo. CAT and DDIT4 expression in spermatozoa were higher in smokers than in nonsmokers, but were not related to DNA damage. CAT and DDIT4 expression were inversely related with sperm count (P = 0.039 and 0.024 resp.), but no effect was observed for SOD2 expression. These data indicate that spermatozoa of smokers encounter higher levels of oxidative stress. Expression of antioxidant enzymes and seminal vitamin C were insufficient to provide full protection of spermatozoa against DNA damage.     

Dietary flavonoids induce MLL translocations in primary human CD34+ cells

Genetic abnormalities leading to infant leukemias already occur during fetal development and often involve rearrangements of the mixed-lineage leukemia (MLL) gene. These rearrangements resemble the aberrations observed in therapy-related leukemias following treatment with topoisomerase II (topoII)-inhibiting agents such as etoposide. Since flavonoids are potent topoII inhibitors, we examined the role of three widely consumed dietary flavonoids (quercetin, genistein and kaempferol) on the development of MLL rearrangements in primary human CD34(+) cells. Using the neutral Comet assay, we demonstrated a dose-dependent double-strand break (DSB) formation after exposure to flavonoids. An incorrect repair of these DSBs resulted in chromosomal translocations that co-localized with those identified in infant leukemias. Most of these translocations were formed by microhomology-mediated end joining. Moreover, in all but one translocation, SINE/Alu or LINE/L1 repetitive elements were present in at least one side of the breakpoint junction. Beside MLL translocations, fluorescence in situ hybridization analysis demonstrated monosomy or trisomy of MLL in 8-10% of the quercetin-exposed CD34(+) cells. Our study demonstrates that biologically relevant concentrations of flavonoids can induce MLL abnormalities in primary hematopoietic progenitor cells. This is particularly alarming knowing that the differences in metabolism and excretion rate between mother and fetus can lead to a higher flavonoid concentration on the fetal side. Therefore, it is important to raise public awareness and set guidelines for marketing flavonoid supplements to reduce the risk of infant leukemias.     

Origin of ganglioside complex antibodies in Guillain-Barré syndrome

The origin of antibodies to ganglioside complexes, as new immunotargets for Guillain-Barré syndrome (GBS), is unknown. This was investigated in 21 GBS patients from which Campylobacter jejuni was isolated. Two of these patients had serum IgG to the GM1/GD1a complex and two other patients had IgG to the GQ1b/GD1a complex. These pairs of patients were clinically distinct. These antibodies all cross-reacted to lipo-oligosaccharides (LOS) from the autologous C. jejuni strain. Previous mass spectrometry studies on these LOS showed the presence of oligosaccharides with a similar structure, further supporting the hypothesis that in these patients LOS induced the ganglioside complex antibodies.     

Polymorphisms in genes of the renin‐angiotensin‐aldosterone system and renal cell cancer risk: Interplay with hypertension and intakes of sodium,potassium and fluid

Hypertension is an established risk factor for renal cell cancer (RCC). The renin‐angiotensin‐aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55 to 69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM® MassARRAY® platform for a literature‐based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow‐up, Cox regression analyses were conducted using a case‐cohort approach including 3,583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs. GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49–1.00)], whereas AGTR1_rs5186 (CC vs. AA) increased RCC risk [HR(95%CI): 1.49(1.08–2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG + AA vs. GG) was modified by hypertension (p interaction = 0.039). SNP‐diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology.     

In utero Exposure to Genotoxicants Leading to Genetic Mosaicism: An Overlooked Window of Susceptibility in Genetic Toxicology Testing?

In utero development represents a sensitive window for the induction of mutations. These mutations may subsequently expand clonally to populate entire organs or anatomical structures. Although not all adverse mutations will affect tissue structure or function, there is growing evidence that clonally expanded genetic mosaics contribute to various monogenic and complex diseases, including cancer. We posit that genetic mosaicism is an underestimated potential health problem that is not fully addressed in the current regulatory genotoxicity testing paradigm. Genotoxicity testing focuses exclusively on adult exposures and thus may not capture the complexity of genetic mosaicisms that contribute to human disease. Numerous studies have shown that conversion of genetic damage into mutations during early developmental exposures can result in much higher mutation burdens than equivalent exposures in adults in certain tissues. Therefore, we assert that analysis of genetic effects caused by in utero exposures should be considered in the current regulatory testing paradigm, which is possible by harmonization with current reproductive/developmental toxicology testing strategies. This is particularly important given the recent proposed paradigm change from simple hazard identification to quantitative mutagenicity assessment. Recent developments in sequencing technologies offer practical tools to detect mutations in any tissue or species. In addition to mutation frequency and spectrum, these technologies offer the opportunity to characterize the extent of genetic mosaicism following exposure to mutagens. Such integration of new methods with existing toxicology guideline studies offers the genetic toxicology community a way to modernize their testing paradigm and to improve risk assessment for vulnerable populations. Environ. Mol. Mutagen. 61:55–65, 2020. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.     

High risk of stent thrombosis in the first 6 months after coronary stenting

Objectives

To estimate the incidence of stent thrombosis (ST) after early discontinuation of clopidogrel.

Background

Premature discontinuation of clopidogrel is the strongest risk factor for ST. In contrast, recent studies suggest that shorter dual antiplatelet therapy (DAPT) can be discontinued as soon as 3 months after stenting. However, these studies included very few ACS patients and were not powered for ST. Hence, little is known about the occurrence of ST in high‐risk populations when DAPT is discontinued early.

Methods

This is a subanalysis of The Dutch ST Registry 437 ST cases (mainly first‐generation DES and BMS). Acute coronary syndrome was the indication for index‐PCI in 74% of the patients. Clopidogrel discontinuation rates in ST patients and matched controls were used to calculate the absolute incidence of ST after early clopidogrel discontinuation.

Results

The overall rate of ST after cessation of clopidogrel was 4.6% (95%CI: 3.9‐5.4%), as compared to 1.7% (95%CI: 1.5‐1.9%) in patients who did not discontinue clopidogrel. The incidence of ST was 35.4% when clopidogrel was discontinued in the first 30 days after index‐PCI declining to 11.7% when clopidogrel was discontinued in the first 180 days.

Conclusions

This dedicated ST registry shows that ST rates were very high when clopidogrel was discontinued before 6 months after index‐PCI and therefore suggests that clopidogrel discontinuation in the first 6 months after ACS should be avoided.

     

Combining Intracavernous Injection and External Vacuum as Treatment for Erectile Dysfunction

We studied the effect of combining intracavernous injection and an external vacuum in 10 men with erectile dysfunction who previously failed attempts at treatment with either method as single therapy. We measured the length, circumference and buckling pressure of the penis at baseline, after applying negative pressure (250 mm. Hg for 2 minutes), 15 minutes after intracavernous injection of 60 mg. papaverine or 30 microgram prostaglandin E1 and after combining both modalities. No patient achieved adequate rigidity (defined as a penile buckle pressure greater than 450 gm.) with single therapy. The mean buckle pressure using vacuum alone was 125.0 plus/minus 53.6 gm. After intracavernous injection the mean buckle pressure was 117.0 plus/minus 38.3 gm. In contrast, all 10 subjects responded to combination therapy with a mean buckle pressure of 565.0 plus/minus 56.8 gm. (p less than 0.0001). After 10 months of followup 3 subjects were still using the combination and were satisfied with the erectile response, 1 found that he no longer needed the addition of external vacuum after using combination therapy for 3 months, 1 used the combination for 9 months and then stopped because of an intervening acute illness, 1 lost the partner due to death, 2 found combination therapy to be too cumbersome and 2 were lost to followup. We conclude that external vacuum devices can augment a partial response to intracavernous injection and the combination may be an alternative treatment before intrapenile prosthesis implantation.