The somatotropic axis [including growth hormone (GH), GH receptor, and insulin-like growth factor (IGF)-I] is uncoupled in high-producing cows in early lactation so that the liver fails to respond to GH and produces less IGF-I. This uncoupling was implicated in the process of nutrient partitioning, enabling high milk production. Different genetic selection goals may affect functional components of the somatotropic axis. Thus, the somatotropic axis was examined in diverse genetic strains of dairy cows [North American Holstein 1990 (NA90), New Zealand Holstein-Friesian 1990 (NZ90), and New Zealand Holstein-Friesian 1970 (NZ70)] that were managed similarly within a pasture-based system but were offered feed allowances commensurate with their genetic ability to produce milk. The NA90 cows produced more milk (26.2 +/- 0.3, 24.1 +/- 0.3, and 20.1 +/- 0.4 kg/d, for NA90, NZ90, and NZ70, respectively), but had lower milk fat percentages (4.28 +/- 0.03, 4.69 +/- 0.03, and 4.58 +/- 0.04 kg/d for NA90, NZ90, and NZ70, respectively) compared with both NZ strains. Milk protein percentages (3.38 +/- 0.02, 3.52 +/- 0.02, and 3.29 +/- 0.03 kg/d for NA90, NZ90, and NZ70, respectively) were greater for NZ90 cows. During early lactation (wk 2 to 6), the total net energy produced in milk was greater in NA90 compared with NZ90 or NZ70 cows, but total net energy in milk after wk 6 was equivalent for NA90 and NZ90 cows. The greater milk production in early lactation in NA90 cows was associated with lower body condition scores (BCS; 1 to 10 scale; 4.0 +/- 0.1) elevated blood GH concentrations (1.6 +/- 0.1 ng/mL), and low blood IGF-I concentrations (14.8 +/- 1.1 ng/mL), indicating an uncoupled somatotropic axis. In comparison, the NZ70 cows retained a coupled somatotropic axis during early lactation, maintaining greater BCS (4.6 +/- 0.1), lower blood GH (0.7 +/- 0.1 ng/mL), and greater blood IGF-I (21.9 +/- 1.2 ng/mL). The degree of uncoupling in NZ90 cows was intermediate between the other 2 strains. Additional feed allowance failed to change blood IGF-I concentrations in NA90 cows but increased IGF-I concentrations in NZ90 cows (20.9 +/- 1.4 and 13.2 +/- 1.4 ng/mL for the high and low feed allowance, respectively). Furthermore, additional feed allowance in NZ90 cows lessened BCS loss in early lactation, but did not affect BCS loss in NA90 cows. Functional components of the somatotropic axis differed for the respective strains and were consistent with strain differences in milk production, BCS, and feed allowance.
Background and objective: Vitamin D regulates the production of the antimicrobial peptides cathelicidin and beta-defensin-2, which play an important role in the innate immune response to infection. We hypothesized that vitamin D deficiency would be associated with lower levels of these peptides and worse outcomes in patients admitted to hospital with community acquired pneumonia. Methods: Associations between mortality and serum levels of 25-hydroxyvitamin D, cathelicidin and betadefensin-2 were investigated in a prospective cohort of 112 patients admitted with community acquired pneumonia during winter. Results: Severe 25-hydroxyvitamin D deficiency (<30 nmol/L) was common in this population (15%) and was associated with a higher 30-day mortality compared with patients with sufficient 25-hydroxyvitamin D (>50 nmol/L) (odds ratio 12.7, 95% confidence interval: 2.2-73.3, P = 0.004). These associations were not explained by differences in age, comorbidities, or the severity of the acute illness. Neither cathelicidin nor beta-defensin-2 levels predicted mortality, although there was a trend towards increased mortality with lower cathelicidin (P = 0.053). Neither cathelicidin nor beta-defensin-2 levels correlated with 25-hydroxyvitamin D. Conclusions: 25-hydroxyvitamin D deficiency is associated with increased mortality in patients admitted to hospital with community acquired pneumonia during winter. Contrary to our hypothesis, 25-hydroxyvitamin D levels were not associated with levels of cathelicidin or beta-defensin-2.
Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10−10 mutations/bp/generation for recently transmitted tuberculosis and 7.3X10−11 mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10−11 mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques.
We conclude that the use of PCR (for the 16S ribosomal DNA in the plasma) was significantly more sensitive than the use of conventional blood culturing techniques for the detection of bacteremia in seriously ill patients. This could prove to be a valuable adjunct to conventional blood cultures.
The objective of this study was to compare the clinical and bacteriological cure rates of cows with clinical mastitis following treatment with either tylosin base (5 g injected 3 times at 24-h intervals; n = 306) or penethamate hydriodide (5 g injected 3 times at 24-h intervals; n = 289). Duplicate milk samples were collected before treatment and again 14 +/- 3 and 21 +/- 3 d later for microbiological analysis. Only those quarters from which gram-positive mastitis pathogens were isolated before treatment were included in the analyses. Streptococcus uberis was the most prevalent isolate. The number of cows with clinical failure (i.e., retreated within 21 d of enrollment) did not differ between treatments (64 vs. 63, respectively). At the quarter level, there was no difference in the proportion of bacteriological cure between treatments (81.2 vs. 83.8% for penethamate hydriodide or tylosin, respectively). The proportions of clinical and bacteriological cure were influenced by age, herd, severity of mastitis, number of glands within the cow with clinical mastitis, bacterial species, and days postpartum at enrollment. There was no difference between treatment groups for SCC (4.46 vs. 4.44 +/- 0.08, mean +/- standard error of the difference in ln SCC for cows treated with penethamate hydriodide or tylosin, respectively) or production of milk solids (1.45 vs. 1.48 +/- 0.02 kg/d of milk fat + protein, for the penethamate hydriodide or tylosin treatment, respectively). Overall, there was no difference in the proportions of clinical failure (17.3 vs. 16.5% of cows treated with penethamate hydriodide or tylosin, respectively) or bacteriological cure (79.8 vs. 82.0% of cows treated with penethamate hydriodide or tylosin, respectively), or in SCC or milk production between dairy cows with clinical mastitis and those treated for clinical mastitis with 1 of 2 parenteral antibiotic therapies.
The VapBC toxin-antitoxin (TA) family is the largest of nine identified TA families. The toxin, VapC, is a metal-dependent ribonuclease that is inhibited by its cognate antitoxin, VapB. Although the VapBCs are the largest TA family, little is known about their biological roles. Here we describe a new general method for the overexpression and purification of toxic VapC proteins and subsequent determination of their RNase sequence-specificity. Functional VapC was isolated by expression of the nontoxic VapBC complex, followed by removal of the labile antitoxin (VapB) using limited trypsin digestion. We have then developed a sensitive and robust method for determining VapC ribonuclease sequence-specificity. This technique employs the use of Pentaprobes as substrates for VapC. These are RNA sequences encoding every combination of five bases. We combine the RNase reaction with MALDI-TOF MS to detect and analyze the cleavage products and thus determine the RNA cut sites. Successful MALDI-TOF MS analysis of RNA fragments is acutely dependent on sample preparation methods. The sequencespecificity of four VapC proteins from two different organisms (VapC PAE0151 and VapC PAE2754 from Pyrobaculum aerophilum, and VapC Rv0065 and VapC Rv0617 from Mycobacterium tuberculosis) was successfully determined using the described strategy. This rapid and sensitive method can be applied to determine the sequence-specificity of VapC ribonucleases along with other RNA interferases (such as MazF) from a range of organisms.
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