Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Reproductive seasonality, sex ratio and philopatry in Argentina's common vampire bats.

Common vampire bats (Desmodus rotundus) are a key rabies vector in South America. Improved management of this species requires long-term, region-specific information. To investigate patterns of demography and dispersal, we analysed 13 642 captures of common vampire bats in Northern Argentina from the period 1969-2004. In contrast with findings from more tropical regions, we found reproductive seasonality with peak pregnancy in September and peak lactation in February. Curiously, sex ratios were consistently male-biased both in maternity roosts and at foraging sites. Males comprised 57% of 9509 adults caught at night, 57% of 1078 juveniles caught at night, 57% of 603 juveniles caught in roosts during the day, and 55% of 103 newborns and mature fetuses. Most observed roosts were in man-made structures. Movements of 1.5-54 km were most frequent in adult males, followed by young males, adult females and young females. At night, males visited maternity roosts, and non-pregnant, non-lactating females visited bachelor roosts. Males fed earlier in the night. Finally, we report new longevity records for free-ranging vampire bats: 16 and 17 years of age for a female and male, respectively. Our results are consistent with model predictions that sex-biased movements might play a key role in rabies transmission between vampire bat populations.

Therapeutic implications of gentamicin accumulation in severly diseased kidneys.

We evaluated the influence of severe disease in human kidneys (12 patients) on gentamicin sulfate accumulation characteristics in such tissue and compared the results with intrarenal tissue concentration data derived from the study of healthy dogs (54 kidneys) during variation in hydration and urinary pH. Our results indicate that, in the management of pyelonephritis complicating preexisting renal disease, if the minimal inhibitory gentamicin concentration for an infecting organism is greater than the usual therapeutic an nontoxic serum levels of the compound, then it may be appropriate to use alternate antibiotics that demonstrate lesser reduction in tissue drug accumulation in diseased kidneys.

Therapeutic implications of doxycycline and cephalothin concentrations in the female genital tract.

The pharmacokinetics of doxycycline and cephalothin in genital tissues and serum were evaluated in 38 patients undergoing hysterectomy. Antibiotic concentrations in the ovary, fallopian tube, myometrium, cervix, and endometrium were measured at varying intervals after antibiotic administration. Cephalothin concentrations in tissues were critically dependent on the time interval between preoperative antibiotic administration and removal of the genital tract tissues, whereas doxycycline concentrations in tissues were consistently reproducible in the time frame evaluated (1/2 to 4 1/2 hours after drug administration). Doxycycline endometrial concentrations were consistently higher than those measured elsewhere in the genital tract (P less than 0.05). These results are of importance in a reassessment of traditional approaches to antibiotic use in gynecologic surgery and in the management of pelvic inflammatory disease (PID).

Dibekacin intrarenal distribution characteristics and renal cortical elution kinetics. Comparison with gentamicin and tobramycin.

Dibekacin (3',4-dideoxykanamycin B) is a new semisynthetic aminoglycoside developed in Japan and one which has found wide clinical acceptance in that country. The antibacterial activity of this compound indicates that it is relatively similar to gentamicin. Since it appears that the intrarenal distributional characteristics and renal cortical kinetics of aminoglycosides provide some predictive information concerning the clinical incidence of nephrotoxicity, we designed a series of pharmacokinetic studies in healthy mongrel dogs which would define such kinetic information for dibekacin and would contrast the results with similar studies for gentamicin and tobramycin. The renal cortical kinetics of dibekacin, as developed in these studies, show that in a canine model the behavior of dibekacin is similar to that of gentamicin and significantly different from tobramycin. Dibekacin and gentamicin show reproducibly higher renal cortical tissue concentrations than tobramycin in both the acute infusion studies and multiple dosing studies. The results suggest that dibekacin may possess the same inherent nephrotoxic potential as that of gentamicin. In order to show any difference in clinical toxicity between gentamicin and dibekacin, a very extensive randomized, double-blind, prospective clinical trial of efficacy and toxicity will be needed.

Factors affecting serum oxytetracycline levels in beef calves.

Fifteen Aberdeen Angus steers, 295-364 kg, were dosed with either 4.4 or 11 mg of oxytetracycline hydrochloride/kg im. The antimicrobial activity of the serum was determined periodically, and the resulting data were treated statistically to determine the sources of variation. Variance in serum levels of oxytetracycline activity was attributed to dose, time of bleeding, order of dosing, animal, and assay. The total variance component was proportionately greater for the 11-mg/kg dose than for the 4.4-mg/kg dose. Animal variance increased with the higher dose level of oxytetracycline. The influence of dose on serum level was tested by applying a t test to the mean serum levels and their standard deviations at each bleeding time. The 4.4- and 11-mg/kg serum levels were significantly different (p less than 0.01) at all bleeding times. The 4.4-mg/kg serum levels mutliplied by 2.5 were not significantly different (p less than 0.05) from the 11-mg/kg serum levels at all bleeding times.

Pharmacokinetic characteristics of doxycycline accumulation in normal and severely diseased kidneys.

Intrarenal concentrations of doxycycline were measured in 48 normal canine kidneys during wide variations in urine pH and the systemic state of hydration of the experimental animals. The results were compared with the renal parenchymal levels achieved in 10 severely diseased human kidneys. Although the state of hydration, the urine pH, and renal disease all significantly influenced the urinary concentrations and rate of renal clearance of doxycycline, there was no detectable difference between concentrations in normal renal tissue and those in severely diseased kidneys. This result is in contradistinction of the findings for previously evaluated antibiotics. The levels of doxycycline measured in renal tissue averaged twice the concentration in serum without notable difference among levels in renal cortex, medulla, and papilla. Prospective clinical trials will be necessary for identification of any solid correlation between the remarkable characteristics of accumulation of doxycycline in diseased renal parenchymal tissue and the clinical, therapeutic importance of such an observation.

Comparison of Microbiological Methods for Detecting Penicillin and Penicillin-Like Antibiotic Residues in Milk.

Five microbiological methods for detecting residues of penicillin and penicillin-like antibiotics were compared, and the relative incidence of residues in whole milk samples was determined. Five groups of 10 lactating cows each and five commercial antibiotic products (penicillin G in oil, penicillin G in a water-dispersible oil base, cloxacillin, cephapirin and ampicillin) used for the treatment of mastitis were studied. Milk samples collected from the cows were tested for antibiotic content by the Sarcina lutea or Bacillus subtilis cylinder plate, International Dairy Federation-Association of Official Analytical Chemists (IDF-AOAC) Bacillus stearothermophilus ATCC 10149 disc plate, Delvotest-P, Antibiotic Residue Branch (ARB) B. stearothermophilus C 953 quantitative disc plate and ARB B. stearothermophilus C 953 quantitative cylinder plate methods. All samples tested by the original S. lutea or B. subtilis cylinder plate methods, with the exception of the penicillin G in oil product (Uni-Biotic), were free of antibiotic residues and showed no inhibitors beyond the labeled milk withdrawal time. The newer, more sensitive official IDF-AOAC method, Delvotest-P and both ARB B. stearothermophilus quantitative disc and cylinder plate methods detected measurable amounts of cephapirin and penicillin G in the post-treatment milk for one to three additional milkings beyond the labeled milk discard time. Cloxacillin, as determined by the ARB B. stearothermophilus cylinder plate method, was generally depleted by 48 h. The excretion rate of ampicillin product coincided with the labeled milk discard time. The level of detection of both disc plate methods and Delvotest-P for cephapirin and ampicillin was comparable. Variations in the concentration in milk and the persistence of two penicillin G products were probably due to differences in the formulation and the dosing regimen. Inhibitory substances and non-specific reactions were observed with the IDF-AOAC disc method, the Delvotest-P and both ARB B. stearothermophilus methods in some control and post-treatment milk samples. These results are consistent with reports of other investigators and suggest that the use of more sensitive procedures for monitoring antibiotic residues in milk may result, for some infusion preparations, in an increased incidence of violative residues of penicillin G and cephapirin.