Balancing dairy cattle diets for rumen nitrogen and methionine or all essential amino acids relative to metabolizable energy.

Improving the ability of diet formulation models to more accurately predict AA supply while appropriately describing requirements for lactating dairy cattle provides an opportunity to improve animal productivity, reduce feed costs, and reduce N intake. The goal of this study was to evaluate the sensitivity of a new version of the Cornell Net Carbohydrate and Protein System (CNCPS) to formulate diets for rumen N, Met, and all essential AA (EAA). Sixty-four high-producing dairy cattle were randomly assigned to 1 of the 4 following diets in a 14-wk longitudinal study: (1) limited metabolizable protein (MP), Met, and rumen N (Base), (2) adequate Met but limited MP and rumen N (Base + M), (3) adequate Met and rumen N, but limited MP (Base + MU), and (4) adequate MP, rumen N, and balanced for all EAA (Positive). All diets were balanced to exceed requirements for ME relative to maintenance and production, assuming a nonpregnant, 650-kg animal producing 40 kg of milk at 3.05% true protein and 4.0% fat. Dietary MP was 97.2, 97.5, 102.3, and 114.1 g/kg of dry matter intake for the Base, Base + M, Base + MU, and Positive diets, respectively. Differences were observed for dry matter intake and milk yield (24.1 to 24.7 and 39.4 to 41.1 kg/d, among treatments). Energy corrected milk, fat, and true protein yield were greater (2.9, 0.13, and 0.08 kg/d, respectively) in cows fed the Positive compared with the Base diet. Using the updated CNCPS, cattle fed the Base, Base + M, and Base + MU diets were predicted to have a negative MP balance (-231, -310, and -142 g/d, respectively), whereas cattle fed the Positive diet consumed 33 g of MP/d excess to ME supply. Bacterial growth was predicted to be depressed by 16 and 17% relative to adequate N supply for the Base and Base + M diets, respectively, which corresponded with the measured lower apparent total-tract NDF degradation. The study demonstrates that improvements in lactation performances can be achieved when rumen N and Met are properly supplied and further improved when EAA supply are balanced relative to requirements. Formulation using the revised CNCPS provided predictions for these diets, which were sensitive to changes in rumen N, Met, all EAA, and by extension MP supply.

Enzymatic debridement in critically injured burn patients - Our experience in the intensive care setting and during burn resuscitation.

BACKGROUND: Much of the recent literature on bromelain based enzymatic debridement of burn injury has focused on its use in smaller burn injury and specialist areas such as the hands or genitals (Krieger et al., 2012; Schulz et al., 2017a,b,c,d). This is despite the original papers describing its use in larger burn injury (Rosenberg et al., 2004, 2014). The current EMA license for Nexobrid™ advises that it should not be used for burn injuries of more than 15% TBSA and should be used with caution in patients with pulmonary burn trauma and suspected pulmonary burn trauma. The original safety and efficacy trial of NexoBrid™ limited its use to 15% TBSA aliquots with concern regarding the effect of bromelain on coagulation. In a European consensus paper of experienced burns clinicians, now on its second iteration, 100% of respondents agreed that "up to 30% BSA can be treated by enzymatic debridement based on individual decision" (Hirche et al., 2017). Hofmaenner et al.'s recent study on the safety of enzymatic debridement in extensive burns larger than 15% provides some further evidence that "bromelain based enzymatic debridement can be carried out safely in large-area burns" (Hofmaenner et al., 2020) but the literature is scant in these larger debridement areas. In our centre we have been using enzymatic debridement for resuscitation level burn injury since 2016. We have gained significant learning in this time; this article aims to describe our current protocol for enzymatic debridement in this patient population and highlight specific learning points that might aid other centres in using enzymatic debridement for larger burn injury. METHOD: We performed a search of the IBID database to identify all adult patients who satisfied the inclusion criteria of resuscitation level burn injury (defined as total burn surface area (TBSA) ≥15% in patients aged >16 years), or level 3 admission following burn injury and who underwent Enzymatic Debridement. A case note review was completed, and details comprising patient demographics, TBSA, mechanism of burn, presence of inhalation injury, sequencing of debridement, length of ICU and hospital stay, blood product utilisation and the need for autografting were recorded. No ethical approval has been sought for this retrospective review. RESULTS: We identified 29 patients satisfying the inclusion criteria (Table 1). Between June 2016 and June 2020 the average total burn size of patients who had at least some of their burn treated by enzymatic debridement increased from 21.4% in 2016/17 to 34.7% in 2019/20. In these patients the actual area treated by enzymatic debridement also increased from 11.9% TBSA to 20.3% TBSA. 19 patients (66%) had enzymatic debridement performed within 24 h of injury, a further 2 patients (7%) within 48 h after injury. Patients were more likely to have enzymatic debridement commenced in the first 24 h after injury if they had circumferential limb injury (39% vs 9%) or were planned for enzyme only debridement (78% vs 28%). Those who were planned for combination enzyme and surgical debridement were more likely to have enzymatic debridement commenced after the first 48 h (75%). We have performed enzymatic debridement overnight on one occasion, for a patient who presented with circumferential limb injury and was determined to undergo urgent debridement. CONCLUSION: Much of the literature has described the use of enzymatic debridement in smaller burns, and specialist areas. However, it is our opinion that the advantages of enzymatic debridement appear to be greater in larger burns with a facility for whole burn excision on the day of admission in the ICU cubicle. We have demonstrated significantly reduced blood loss, improved dermal preservation, reduced need for autografting, and a reduction in the number of trips to theatre. We would advocate that both the team and the patient need to be as prepared as they would be for a traditional surgical excision. The early part of our learning curve for enzymatic debridement in resuscitation level injuries was steep, and we were able to build on experience from managing smaller injuries. We recommend any team wishing to using enzymatic debridement gain experience in the same way and develop robust local pathways prior to attempting use in larger burn injuries.

Assessing the Correlation Between Physical Activity and Quality of Life in Advanced Lung Cancer.

BACKGROUND AND OBJECTIVE: Increasing physical activity (PA) is safe and beneficial in lung cancer (LC) patients. Advanced-stage LC patients are under-studied and have worse symptoms and quality of life (QoL). We evaluated the feasibility of monitoring step count in advanced LC as well as potential correlations between PA and QoL. METHODS: This is a prospective, observational study of 39 consecutive patients with advanced-stage LC. Daily step count over 1 week (via Fitbit Zip), QoL, dyspnea, and depression scores were collected. Spearman rank testing was used to assess correlations. Correlation coefficients (ρ) >0.3 or <-0.3 (more and less correlated, respectively) were considered potentially clinically significant. RESULTS: Most (83%) of the patients were interested in participating, and 67% of those enrolled were adherent with the device. Of those using the device (n = 30), the average daily step count was 4877 (range = 504-12 118) steps/d. Higher average daily step count correlated with higher QoL (ρ = 0.46), physical (ρ = 0.61), role (ρ = 0.48), and emotional functioning (ρ = 0.40) scores as well as lower depression (ρ = -0.40), dyspnea (ρ = -0.54), and pain (ρ = -0.37) scores. CONCLUSION: Remote PA monitoring (Fitbit Zip) is feasible in advanced-stage LC patients. Interest in participating in this PA study was high with comparable adherence to other PA studies. In those utilizing the device, higher step count correlates with higher QoL as well as lower dyspnea, pain, and depression scores. PA monitoring with wearable devices in advanced-stage LC deserves further study.

Effect of feeding different sources of rumen-protected methionine on milk production and N-utilization in lactating dairy cows.

Objectives of this study were to quantify production responses of lactating dairy cows to supplying absorbable Met as isopropyl-2-hydroxy-4-(methylthio)-butanoic acid (HMBi), or rumen-protected Met (RPM, Smartamine M; Adisseo, Alpharetta, GA) fed with or without 2-hydroxy-4-(methylthio)-butanoic acid (HMB), and to determine whether Met supplementation will allow the feeding of reduced dietary crude protein (CP). Seventy cows were blocked by parity and days in milk into 14 blocks and randomly assigned within blocks to 1 of the 5 dietary treatments based on alfalfa and corn silages plus high-moisture corn: 1 diet with 15.6% CP and no Met source (negative control); 3 diets with 15.6% CP plus 0.17% HMBi, 0.06% RPM + 0.10% HMB, or 0.06% RPM alone; and 1 diet with 16.8% CP and no Met supplement (positive control). Assuming that 50% of ingested HMBi was absorbed from the gastrointestinal tract and 80% of the Met in RPM was absorbed at intestine, the HMBi and RPM supplements increased metabolizable Met supply by 9 g/d and improved the Lys:Met ratio from 3.6 to 3.0. After a 2-wk covariate period during which all cows received the same diet, cows were fed test diets continuously for 12 wk. Diet did not affect dry matter intake (mean ± SD, 25.0±0.3 kg/d), body weight gain (0.59±0.2 kg/d), or milk yield (41.7±0.6 kg/d). However, feeding HMBi increased yield of energy-corrected milk and milk content of protein and solids-not-fat. Moreover, trends were observed for increased milk fat content and yield of fat and true protein on all 3 diets containing supplemental Met. Apparent N efficiency (milk N/N intake) was highest on the RPM treatment. Feeding 16.8% CP without a Met source elevated milk urea N and urinary excretion of urea N and total N and reduced apparent N efficiency from 34.5 to 30.2%, without improving production. Overall results suggested that feeding HMBi or RPM would give similar improvements in milk production and N utilization.

High-dose antioxidant administration is associated with a reduction in post-injury complications in critically ill trauma patients.

BACKGROUND: We recently demonstrated a high-dose antioxidant (AO) protocol was associated with reduction in mortality. The purpose of this study was to evaluate the impact of AO on organ dysfunction and infectious complications following injury. PATIENTS AND METHODS: High-dose AO protocol: ascorbic acid 1000 mg q 8 h, alpha-tocopherol 1000 IU q 8 h, and selenium 200 mcg qd for 7-day course. Retrospective cohort study evaluating all patients admitted after protocol implementation (AO+), October 1, 2005 to September 30, 2006. Comparison cohort (AO-): all patients admitted in the year prior to implementation, October 1, 2004 to September 30, 2005. RESULTS: 2272 patients included in the AO+ group, 2022 patients in the AO- group. Demographics and injury severity were similar. Abdominal compartment syndrome (ACS) (2.9% vs. 0.7%, <0.001), surgical site infections (2.7% vs. 1.3%, p=0.002), pulmonary failure (27.6% vs. 17.4%, p<0.001), and ventilator-dependent respiratory failure (10.8% vs. 7.1%, p<0.001) were significantly less in the AO+ group. Multivariate regression showed 53% odds reduction in abdominal wall complications and 38% odds reduction in respiratory failure in the AO+ group. CONCLUSIONS: Implementation of a high-dose AO protocol was associated with a reduction in respiratory failure and ventilator-dependence. In addition, AO were associated with a marked decrease in abdominal wall complications, including ACS and surgical site infections.

Effects of providing two forms of supplemental methionine to periparturient Holstein dairy cows on feed intake and lactational performance.

Eighteen primiparous and 42 multiparous Holstein cows were blocked according to parity and expected calving date and assigned randomly to 1 of 3 dietary treatments: 1) a basal diet (negative control), 2) the basal diet plus 2-hydroxy-4-methylthio butanoic acid isopropyl ester (MetaSmart, Adisseo Inc., Antony, France), or 3) the basal diet plus rumen-protected Met (Smartamine M, Adisseo Inc., Alpharetta, GA). Treatments were initiated 21 d before expected calving and continued through 140 d postpartum. Diets were similar in ingredient and chemical composition, except for the content of Met in metabolizable protein. MetaSmart [0.35% prepartum and 0.54% postpartum in diet dry matter (DM)] and Smartamine M (0.06% prepartum and 0.10% postpartum in diet DM) were added to the basal diet in amounts needed to achieve a 3.0:1 ratio of Lys to Met in metabolizable protein. Prepartum DM intake (DMI; 13.5 kg/d), body weight (687 kg), body condition score (3.81), postpartum milk yield (42.0 kg/d), milk fat yield (1,549 g/d), milk fat content (3.66%), milk true protein yield (1,192 g/d), and milk urea N content (12.9 mg/dL) were not different among treatments. Postpartum DMI and body condition score were greater and the ratios of milk:DMI and milk N:feed N were less for cows fed the MetaSmart diet than for cows fed the control and Smartamine M diets. Milk protein content was greater for the Smartamine M (2.87%) and MetaSmart (2.81%) treatments than for the control treatment (2.72%). Concentrations of Met and Met + Cys in total plasma AA were different among treatments, with values for the Smartamine M treatment being the highest, followed by the MetaSmart and control treatments. The results indicated that both MetaSmart and Smartamine M are effective in providing metabolizable Met, but clarification of their relative contributions to metabolizable Met is still needed.

Impact of high-dose antioxidants on outcomes in acutely injured patients.

BACKGROUND: The profound oxidative stress that occurs following injury results in significant depletion of many endogenous antioxidants (vitamin C, E, selenium). Increasing evidence suggests antioxidant supplementation reduces infectious complications and organ dysfunction following injury and hemorrhagic shock. The purpose of this study was to evaluate the impact of high-dose antioxidant administration on the mortality rate of acutely injured patients. METHODS: In October 2005, we implemented a 7-day high-dose antioxidant protocol for acutely injured patients admitted to our trauma center. A retrospective cohort study, evaluating all patients admitted to the trauma service between October 2005 and September 2006 following protocol implementation (AO+), was performed. The comparison cohort (AO-) was made up of those patients admitted in the year prior to protocol implementation. RESULTS: A total of 4,294 patients met criteria (AO+, N = 2,272; AO-, N = 2022). Hospital (4 vs 3 days, P < .001) and ICU (3 vs 2 days, P = .001) median length of stays were significantly shorter in the AO+ group. Mortality was significantly lower in the AO+ group (6.1% vs 8.5%, P = .001), translating into a 28% relative risk reduction for mortality in patients exposed to high-dose antioxidants. After adjusting for age, gender, and probability of survival, AO exposure was associated with even lower mortality (OR 0.32, 95% CI 0.22-0.46). Patients with an expected survival <50% benefited most (OR 0.24, 95% CI 0.15-0.37). CONCLUSIONS: A high-dose antioxidant protocol resulted in a 28% relative risk reduction in mortality and a significant reduction in both hospital and ICU length of stay. This protocol represents an inexpensive intervention to reduce mortality/morbidity in the trauma patient.

Antihyperglycemic activities of cryptolepine analogues: an ethnobotanical lead structure isolated from Cryptolepis sanguinolenta.

Cryptolepine (1) is a rare example of a natural product whose synthesis was reported prior to its isolation from nature. In the previous paper we reported the discovery of cryptolepine's antihyperglycemic properties. As part of a medicinal chemistry program designed to optimize natural product lead structures originating from our ethnobotanical and ethnomedical field research, a series of substituted and heterosubstituted cryptolepine analogues was synthesized. Antihyperglycemic activity was measured in vitro and in an NIDDM mouse model to generate the first structure-bioactivity study about the cryptolepine nucleus.

Antiviral phenylpropanoid glycosides from the medicinal plant Markhamia lutea.

Three new phenylpropanoid glycosides, named luteoside A (3), luteoside B (4), and luteoside C (5), were isolated together with the known compounds verbascoside (1) and isoverbascoside (2) from the roots of the medicinal plant Markhamia lutea. The structures of the new compounds were determined to be 1-O-(3, 4-dihydroxyphenyl)ethyl beta-D-apiofuranosyl(1-->2)-alpha-l-rhamnopyranosyl(1-->3)-4-O- caffeo yl-6-acetyl-beta-d-glucopyranoside, 1-O-(3,4-dihydroxyphenyl)ethyl beta-d-apiofuranosyl(1-->2)-alpha-l-rhamnopyranosyl(1-->3)-6-O- caffeo yl-beta-d-glucopyranoside, and 1-O-(3,4-dihydroxyphenyl)ethyl beta-D-apiofuranosyl(1-->2)-alpha-l-rhamnopyranosyl(1-->3)-6-O- ferulo yl-beta-d-glucopyranoside, respectively, on the basis of chemical and spectroscopic data. All five phenylpropanoid glycosides exhibited potent in vitro activity against respiratory syncytial virus.

Interactions of ruminally protected methionine and lysine with protein source or energy level in the diets of cows.

Interactions between supplementation with ruminally protected Met and Lys and the nature of protein or energy concentration of the diet were studied using 16 and 12 multiparous lactating dairy cows in two trials of 8 and 12 wk, respectively, commencing on approximately d 40 of lactation. In trial 1, cows received a semicomplete diet plus concentrates. The diet consisted of 62 to 63% corn silage, 2.2% corn gluten meal, .4% urea, 11% soybean meal (untreated or treated with formaldehyde), and 23 to 24% barley. In trial 2, cows received a complete diet with corn silage, untreated and formaldehyde-treated soybean meal, and barley in the ratio 78:12:9:0 or 49:13:4:33. All treatments were replicated in a 4 x 4 Latin square design. In both trials, Met plus Lys (10 g/d of intestinally available Met and 30 g/d of Lys) has no significant effect on DMI, milk yield, fat content, casein as a percentage of true protein, or urea content of the milk. Mean increase of milk protein yield was 46 g/d with Met plus Lys, and mean increase of true protein content was 1.1 g/kg of milk. The increase in content of milk true protein was greater for cows receiving the low energy diet. Protein source had no effect on milk yield or composition. Glucose, urea, NEFA, BHBA, and total free AA in plasma were unaffected by supplementation of ruminally protected Met plus Lys. However, concentrations of Met and Lys in blood were slightly, but not significantly, higher in supplemented cows.

Biochemical pharmacology of the lipophilic antifolate, trimetrexate.

Trimetrexate is a novel lipophilic folate antagonist that causes growth inhibition, inhibition of nucleic acid biosynthesis, and cytotoxicity at nanomolar concentrations in tissue cultures. The potency of trimetrexate cytotoxicity against most cell lines is greater than that of methotrexate. Trimetrexate has antitumor activity in vivo in several murine leukemia and solid tumor systems, including tumors in which methotrexate is inactive. Antitumor activity was seen following oral, intravenous, or intraperitoneal administration. Trimetrexate causes a pronounced and early depression in incorporation of deoxyuridine into DNA. In tumor cell lines resistant to methotrexate because of a drug transport defect, trimetrexate retains activity. In many such cases the methotrexate-resistant tumors show collateral sensitivity to trimetrexate. In methotrexate-resistant cells with impaired drug transport, trimetrexate sensitivity was even more pronounced when cells were grown in folate-free medium supplemented with physiological levels of tetrahydrofolate cofactor. In the human tumor stem cell colony assay, trimetrexate, at concentrations achievable in vivo, gave activity against many human tumors, including samples that were unresponsive to methotrexate. Trimetrexate crosses the blood-brain barrier, and at very high doses may cause neurotoxicity. At conventional doses the primary toxic effects in mice are gastrointestinal. This toxicity is reversible at therapeutic doses. Unlike earlier lipophilic antifolates, trimetrexate has rapid plasma clearance (t1/2 in mice of 45 minutes). Trimetrexate is a tight-binding competitive inhibitor of dihydrofolate reductase. The Ki,slope for inhibition of the human enzyme was 4 X 10(-11) M. A dose-dependent decrease in cellular purine ribonucleotide pools is given by trimetrexate. Pyrimidine ribonucleotide pools tend to increase in treated cells. Trimetrexate caused a marked depression of cellular pools of dTTP and dGTP, and a lesser depression in dATP. Cytotoxicity of trimetrexate in vitro was prevented by leucovorin. Leucovorin also protected mice from trimetrexate toxicity. Thymidine protected cells from lethal effects of low concentrations of trimetrexate, but not from high concentrations. The combination of thymidine and hypoxanthine completely protected cells from low and high concentrations of trimetrexate. A new, stable and highly water-soluble formulation of trimetrexate has been developed. Because of the interesting biochemical and pharmacological properties of trimetrexate, and its experimental antitumor activity, clinical trials are planned.