The impact of CYP2C9 genetics and oral contraceptives on cytochrome P450 2C9 phenotype.

CYP2C9-dependent drug metabolism is subject to large interindividual variation. To some extent, this is explained by genetic polymorphism with expression of enzyme variants that differ in catalytic activity. The aim of this study was to characterize the variation in CYP2C9 phenotype in relation to genotype, with further analysis of the CYP2C9 gene in metabolic outliers. A study population of 126 healthy white subjects were recruited and genotyped for the variant alleles, CYP2C9*1-3. In CYP2C9 phenotyping with losartan, three subpopulations were distinguished that differed in the number of CYP2C9*3 alleles (0, 1, or 2). A three-fold higher metabolic ratio (MR; urinary losartan/carboxymetabolite) was found comparing CYP2C9*1/*3 (n = 20) to CYP2C9*1/*1 (n = 81), but there was considerable variation within each genotype. Subjects genotyped as CYP2C9*1/*1, but with an unexpectedly slow oxidation of losartan, were selected for DNA-sequencing analysis of the CYP2C9 gene. Interestingly, single nucleotide polymorphisms (SNPs) could not be identified either in the 5'-flanking region, the nine exons, or exon-intron boundaries. However, sequencing of the CYP2C9 gene was also carried out in patients genotyped as CYP2C9*1/*1 but with an exceptionally low steady-state clearance of S-warfarin. Here, five different SNPs were identified. In further analysis of the healthy volunteers, it became evident that women on oral contraceptives (OCs) had slower oxidation of losartan (MR of losartan: 1.7) than women without OCs (MR of losartan: 0.86). This novel finding was not explained by a different frequency of variant alleles. In summary, CYP2C9 genotype and oral contraceptives both contribute to a large interindividual variation in CYP2C9 activity.     

Dietary sodium restriction specifically potentiates left ventricular ACE inhibition by zofenopril, and is associated with attenuated hypertrophic response in rats with myocardial infarction.

INTRODUCTION: In patients with myocardial infarction (MI)-induced heart failure, angiotensin-converting enzyme (ACE) inhibitors are proven effective therapy in inhibiting the progression towards overt heart failure. However, the prognosis in these patients is still very poor, and optimisation of therapy is warranted. The antihypertensive and renoprotective effects of ACE inhibitors (ACE-Is) can be substantially enhanced by dietary sodium restriction. In line with the latter, the aim of the present study was to explore whether dietary sodium restriction enhances the efficacy of ACE-I after MI. METHODS: Rats with MI-induced left ventricular (LV) dysfunction received ACE-I therapy with zofenopril (5.5 mg/kg/day orally), with or without dietary sodium restriction. ACE activity was measured in non-infarcted LV tissue, kidneys and plasma. Effects on cardiac hypertrophy were examined by means of organ weight/body weight ratios. After blood pressure (BP) measurements, functional consequences of therapy were evaluated as LV pressure development in isolated perfused hearts. RESULTS: Dietary sodium restriction alone had no effect on any of the measured parameters, whereas zofenopril alone significantly reduced plasma and kidney ACE activity, but not LV ACE activity, nor LV weight/body weight ratio. However, only when ACE-I therapy was combined with dietary sodium restriction was LV ACE activity significantly reduced. This effect was paralleled by inhibition of LV hypertrophy. BP was reduced after infarction, and further reduced by zofenopril, but not affected by dietary sodium. Neither treatment was associated with effects on the MI-induced reduction of LV function in vitro. CONCLUSIONS: Effects of ACE inhibition with zofenopril can be potentiated by additional dietary sodium restriction. However, these effects were tissue-specific, since LV, but not kidney or plasma, ACE activity was affected by the additional dietary sodium restriction. Effects on LV ACE activity were paralleled by reduced LV hypertrophy. Since the measured parameters did not indicate any adverse side-effects, dietary sodium restriction may provide a safe strategy to improve ACE-I efficacy in patients with infarction-induced LV dysfunction.     

Deconstructing male violence against women: the men stopping violence community-accountability model

Men Stopping Violence (MSV), a 24-year-old metro Atlanta-based organization that works to end male violence against women, uses an ecological, community-based accountability model as the foundation of its analysis of the problem of male violence against women and of its work with individuals and in communities. The MSV community-accountability model of male violence against women offers a view of the cultural and historical mechanisms that support violence against women. The model, and the strategies and programs that have grown out of it, demonstrate the potential for disrupting traditions of abuse and dominance at the individual, familial, local, national, and global levels.     

Long-term outcome after fetal transfusion for hydrops associated with parvovirus B19 infection

OBJECTIVE: To evaluate neurodevelopmental status of children treated with intrauterine red blood cell and platelet transfusion for fetal hydrops caused by parvovirus B19. METHODS: Maternal and neonatal records of all intrauterine transfusions for congenital parvovirus B19 infection in our center between 1997 and 2005 were reviewed. Congenital B19 virus infection was confirmed by the presence of parvovirus B19-specific immunoglobulin M or parvovirus B19 DNA in fetal blood samples. All children underwent a general pediatric and neurological examination. Primary outcome measure was neurodevelopmental status (developmental index by Bayley Scales of Infant Development or Snijders-Oomen test). Secondary outcome measure was general health status of surviving children. RESULTS: A total of 25 intrauterine transfusions were performed in 24 hydropic fetuses. Median fetal hemoglobin concentration, platelet count, and blood pH before intrauterine transfusions were 4.5 g/dL (range 2.4-11.4 g/dL), 79x10(9)/L (range 37-238x10(9)/L) and 7.36 (range 7.31-7.51), respectively. Sixteen survivors aged 6 months to 8 years were included in the follow-up study. Eleven children (68%) were normal, and 5 children (32%) demonstrated a delayed psychomotor development with an suboptimal neurological examination (mild delay n=3, severe delay n=2). Neurodevelopmental status did not correlate with pre-intrauterine transfusion hemoglobin, platelet, or blood pH values. Growth and general health status were normal in all. Two children had minor congenital defects. CONCLUSION: Neurodevelopmental status was abnormal in 5 of 16 survivors and was not related to the severity of fetal anemia and acidemia. We hypothesize that fetal parvovirus B19 infection may induce central nervous system damage. LEVEL OF EVIDENCE: III.     

Phototoxicity of tetracyclines as related to singlet oxygen production and uptake by polymorphonuclear leukocytes

The photo-induced singlet oxygen production of six tetracyclines was measured as tryptophan degradation. Demethylchlortetracycline was the most efficient singlet oxygen producer followed by doxycycline. The least efficient producer was minocycline. Doxycycline, however, was the most potent inducer of photodamage to polymorphonuclear leukocytes (PMNLs) followed by demethylchlortetracycline. Accordingly, the singlet oxygen production during irradiation did not correlate with the induction of photodamage to the PMNLs. However, the uptake of doxycycline by the cells was 3 times higher than that of demethylchlortetracycline, and the tetracycline-induced photodamage to the PMNLs correlated with the product of singlet oxygen production during irradiation and the drug uptake by the cells.     

The photobiology of the human circadian clock

In modern society, the widespread use of artificial light at night disrupts the suprachiasmatic nucleus (SCN), which serves as our central circadian clock. Existing models describe excitatory responses of the SCN to primarily blue light, but direct measures in humans are absent. The combination of state-of-the-art neuroimaging techniques and custom-made MRI compatible light-emitting diode devices allowed to directly measure the light response of the SCN. In contrast to the general expectation, we found that blood oxygen level–dependent (BOLD) functional MRI signals in the SCN were suppressed by light. The suppressions were observed not only in response to narrowband blue light (λ_max: 470 nm) but remarkably, also in response to green (λ_max: 515 nm) and orange (λ_max: 590 nm), but not to violet light (λ_max: 405 nm). The broadband sensitivity of the SCN implies that strategies on light exposure should be revised: enhancement of light levels during daytime is possible with wavelengths other than blue, while during nighttime, all colors are potentially disruptive.

Due to the Earth’s rotation around its axis, many organisms developed an internal clock to anticipate the predictable changes in the environment that occur every 24 h, including the daily light–dark cycle. In mammals, this clock is located in the suprachiasmatic nucleus (SCN), located in the hypothalamus directly above the optic chiasm (1, 2). The SCN receives information from the retina regarding ambient light levels via intrinsically photosensitive retinal ganglion cells (ipRGCs), thus synchronizing its internal clock to the external light–dark cycle. ipRGCs contain the photopigment melanopsin, which is maximally sensitive to blue light, with a peak response to 480-nm light (3, 4). In addition, ipRGCs also receive input from rod cells and cone cells (5–7). The three cone cell subtypes in the human retina respond maximally to 420-nm, 534-nm, and 563-nm light, while rod cells respond maximally to 498-nm light (8). In rodents, input from cone cells renders the SCN sensitive to a broad spectrum of wavelengths (9), while rod cells mediate the SCN’s sensitivity to low-intensity light (10, 11). Recently, these findings in rodents were proposed to translate to humans (12), suggesting that the human clock is not only sensitive to blue light, but may also be sensitive to other colors.In humans, circadian responses to light are generally measured indirectly (e.g., by measuring melatonin levels or 24-h behavioral rhythms). These indirect measures revealed that circadian responses to light in humans are most sensitive to blue light (13–16); however, green light has also been found to contribute to circadian phase shifting and changes in melatonin to a larger extent than would have been predicted based solely on the melanopsin response, suggesting that rods and/or cones may also provide functional input to the circadian system in humans (17). Despite this indirect evidence suggesting that several colors can affect the human circadian clock, this has never been measured directly due to technical limitations. Thus, current guidelines regarding the use of artificial light are based solely on the clock’s sensitivity to blue light. For example, blue light is usually filtered out in electronic screens during the night (18, 19), and blue-enriched light is used by night shift workers to optimize their body rhythm for achieving maximum performance (20–22).The ability to directly image the human SCN in vivo has been severely limited due to its small size and the relatively low spatial resolution provided by medical imaging devices. Previous functional MRI (fMRI) studies using 3-Tesla (3T) scanners were restricted to recording the “suprachiasmatic area,” which encompasses a large part of the hypothalamus and thus includes many other potentially light-sensitive nuclei (23–25). To overcome this limitation, we used a 7T MRI scanner, which can provide images with sufficiently high spatial resolution to image small brain nuclei (26) such as the SCN. Here, we applied colored light stimuli to healthy volunteers using a custom-designed MRI-compatible light-emitting diode (LED) device designed to stimulate specific photoreceptors while measuring SCN activity using fMRI. Using analytical approaches, we then identified the SCN’s response, the smallest brain nucleus that has so far been imaged. We found that the human SCN responds to a broad range of wavelengths (i.e., blue, green and orange light). Surprisingly, we also found that the blood oxygen level–dependent (BOLD) fMRI signal at the SCN is actually suppressed—not activated—by light.