Open Dislocation of the Scaphoid With an Associated Hamate Fracture and Fourth Metacarpal Fracture.

Scaphoid dislocation represents a rare injury with only a few case reports and limited case series reported in the literature. The majority of scaphoid dislocations result from a high-energy trauma causing hyperextension and ulnar deviation of the wrist. The severity of a scaphoid dislocation depends on the degree of periscaphoid ligamentous injury as well as the presence of concomitant injuries, such as axial carpal dissociation. The most common complication after a scaphoid dislocation is scapholunate dissociation, which emphasizes the importance of scapholunate ligament repair/reconstruction in these cases. We report a case of an open scaphoid dislocation with the associated injuries of a hamate fracture and fourth metacarpal fracture treated with an open reduction of the scaphoid, open ligamentous repair and augmentation of the involved carpal ligaments, and open reduction internal fixation of both the hamate and the fourth metacarpal fractures.

Dynamic DNA Methylation in Plant Growth and Development.

DNA methylation is an epigenetic modification required for transposable element (TE) silencing, genome stability, and genomic imprinting. Although DNA methylation has been intensively studied, the dynamic nature of methylation among different species has just begun to be understood. Here we summarize the recent progress in research on the wide variation of DNA methylation in different plants, organs, tissues, and cells; dynamic changes of methylation are also reported during plant growth and development as well as changes in response to environmental stresses. Overall DNA methylation is quite diverse among species, and it occurs in CG, CHG, and CHH (H = A, C, or T) contexts of genes and TEs in angiosperms. Moderately expressed genes are most likely methylated in gene bodies. Methylation levels decrease significantly just upstream of the transcription start site and around transcription termination sites; its levels in the promoter are inversely correlated with the expression of some genes in plants. Methylation can be altered by different environmental stimuli such as pathogens and abiotic stresses. It is likely that methylation existed in the common eukaryotic ancestor before fungi, plants and animals diverged during evolution. In summary, DNA methylation patterns in angiosperms are complex, dynamic, and an integral part of genome diversity after millions of years of evolution.

Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse Intrauterine Environment and Modulated by a Post-Weaning High-Fat Diet.

Adult individuals born with intrauterine growth restriction (IUGR) have physiological maladaptations that significantly increase risk of chronic disease. We suggested that such abnormalities in organ function would alter pharmacokinetics throughout life, exacerbated by environmental mismatch. Pregnant and lactating rats were fed either a purified control diet (18% protein) or low-protein diet (9% protein) to produce IUGR offspring. Offspring were weaned onto either laboratory chow (11% fat) or high-fat diet (45% fat). Adult offspring (5 months old) were dosed with furosemide (10 mg/kg i.p.) and serum and urine collected. The overall exposure profile in IUGR males was significantly reduced due to a ~35% increase in both clearance and volume of distribution. Females appeared resistant to the IUGR phenotype. The effects of the high-fat diet trended in the opposite direction to that of IUGR, with increased drug exposure due to decreases in both clearance (31% males, 46% females) and volume of distribution (24% males, 44% females), with a 10% longer half-life in both genders. The alterations in furosemide pharmacokinetics and pharmacodynamics were explained by changes in the expression of renal organic anion transporters 1 and 3, and sodium-potassium-chloride cotransporter-2. In summary, this study suggests that IUGR and diet interact to produce subpopulations with similar body-weights but dissimilar pharmacokinetic profiles; this underlines the limitation of one-size-fits-all dosing which does not account for physiological differences in body composition resulting from IUGR and diet.

Perinatal growth restriction decreases diuretic action of furosemide in adult rats.

Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. We hypothesize that such renal maladaptations result in altered pharmacologic patterns for life. Maternal protein restriction during gestation and lactation was used to induce perinatal growth restriction in the current study. The diuretic response of furosemide (2mg/kg single i.p. dose) in perinatally growth restricted rats during adulthood was investigated. Diuresis, natriuresis and renal excretion of furosemide were significantly reduced relative to controls, indicative of decreased efficacy. While a modest 12% decrease in diuresis was observed in males, females experienced 26% reduction. It is important to note that the baseline urine output and natriuresis were similar between treatment groups. The in vitro renal and hepatic metabolism of furosemide, the in vivo urinary excretion of the metabolite, and the expression of renal drug transporters were unaltered. Creatinine clearance was significantly reduced by 15% and 19% in perinatally growth restricted male and female rats, respectively. Further evidence of renal insufficiency was suggested by decreased uric acid clearance. Renal protein expression of sodium-potassium-chloride cotransporter, a pharmacodynamic target, was unaltered. In summary, perinatal growth restriction could permanently imprint pharmacokinetic processes affecting drug response.

An ethinyl estradiol-levonorgestrel containing oral contraceptive does not alter cytochrome P4502C9 in vivo activity.

Oral contraceptives have been in wide use for more than 50 years. Levonorgestrel, a commonly employed progestin component of combined oral contraceptives, was implicated in drug-drug interactions mediated via CYP2C9. Although in vitro studies refuted this interaction, there are no confirmatory in vivo studies. In the current study, we examined the phenotypic status of CYP2C9 using low-dose (125 mg) tolbutamide before and after oral contraceptive use in reproductive age women. Blood was collected 24 hours after the tolbutamide oral dose was administered, plasma was isolated, and tolbutamide concentration (C24) was measured using liquid chromatography-mass spectrometry. The natural logarithm of tolbutamide C24, a metric for CYP2C9 phenotype, was found to be equivalent (within 80%-125% equivalency boundaries) before and after oral contraceptive use. In conclusion, levonorgestrel-containing oral contraceptives, the most commonly used form of oral contraception, do not affect the status of the CYP2C9 enzyme. This suggests that it is safe to co-administer levonorgestrel-containing oral contraceptives and CYP2C9 substrates, which include a wide array of drugs.

Maternal low-protein diet alters the expression of real-time quantitative polymerase chain reaction reference genes in an age-, sex-, and organ-dependent manner in rat offspring.

Altered perinatal environment, often manifested as low birth weight, is thought to contribute to greater susceptibility for hypertension, hyperlipidemia, and diabetes as a result of epigenetic modifications and alteration of transcriptional activity for key genes. Real-time polymerase chain reaction is a useful technique for the quantitative determination of differences in transcriptional activity. Real-time quantitative polymerase chain reaction data analyses require normalization of transcriptional activity of target genes to an endogenous control, usually a reference gene. In response to reports of altered expression of reference genes in various experimental models, we hypothesized that adverse perinatal environment alters reference gene expression. We examined the expression of the following reference genes in the offspring of a rodent maternal low-protein diet model: ß-actin, hypoxanthine phosphoribosyltransferase 1, TATA-box-binding protein, glyceraldehyde-3-phosphate dehydrogenase, and glucuronidase-ß in brain, heart, kidneys, and intestines. We found altered expression in brain, heart, and kidneys for each of the reference genes measured; these effects were age, organ, and sex dependent. Glyceraldehyde-3-phosphate dehydrogenase and glucuronidase-ß were found to be the least affected by these variables, whereas hypoxanthine phosphoribosyltransferase 1 was the most inconsistent. Our findings underscore the importance of empirical determination of a reliable reference gene for real-time polymerase chain reaction studies in the low-protein diet model.