Optimizing tuberculosis treatment efficacy: Comparing the standard regimen with Moxifloxacin-containing regimens.

Tuberculosis (TB) continues to be one of the deadliest infectious diseases in the world, causing ~1.5 million deaths every year. The World Health Organization initiated an End TB Strategy that aims to reduce TB-related deaths in 2035 by 95%. Recent research goals have focused on discovering more effective and more patient-friendly antibiotic drug regimens to increase patient compliance and decrease emergence of resistant TB. Moxifloxacin is one promising antibiotic that may improve the current standard regimen by shortening treatment time. Clinical trials and in vivo mouse studies suggest that regimens containing moxifloxacin have better bactericidal activity. However, testing every possible combination regimen with moxifloxacin either in vivo or clinically is not feasible due to experimental and clinical limitations. To identify better regimens more systematically, we simulated pharmacokinetics/pharmacodynamics of various regimens (with and without moxifloxacin) to evaluate efficacies, and then compared our predictions to both clinical trials and nonhuman primate studies performed herein. We used GranSim, our well-established hybrid agent-based model that simulates granuloma formation and antibiotic treatment, for this task. In addition, we established a multiple-objective optimization pipeline using GranSim to discover optimized regimens based on treatment objectives of interest, i.e., minimizing total drug dosage and lowering time needed to sterilize granulomas. Our approach can efficiently test many regimens and successfully identify optimal regimens to inform pre-clinical studies or clinical trials and ultimately accelerate the TB regimen discovery process.

Framework for the assessment of interaction between CO2 geological storage and other sedimentary basin resources.

Sedimentary basins around the world considered suitable for carbon storage usually contain other natural resources such as petroleum, coal, geothermal energy and groundwater. Storing carbon dioxide in geological formations in the basins adds to the competition for access to the subsurface and the use of pore space where other resource-based industries also operate. Managing potential impacts that industrial-scale injection of carbon dioxide may have on other resource development must be focused to prevent potential conflicts and enhance synergies where possible. Such a sustainable coexistence of various resource developments can be accomplished by implementing a Framework for Basin Resource Management strategy (FBRM). The FBRM strategy utilizes the concept of an Area of Review (AOR) for guiding development and regulation of CO2 geological storage projects and for assessing their potential impact on other resources. The AOR is determined by the expected physical distribution of the CO2 plume in the subsurface and the modelled extent of reservoir pressure increase resulting from the injection of the CO2. This information is used to define the region to be characterised and monitored for a CO2 injection project. The geological characterisation and risk- and performance-based monitoring will be most comprehensive within the region of the reservoir containing the carbon dioxide plume and should consider geological features and wells continuously above the plume through to its surface projection; this region defines where increases in reservoir pressure will be greatest and where potential for unplanned migration of carbon dioxide is highest. Beyond the expanse of the carbon dioxide plume, geological characterisation and monitoring should focus only on identified features that could be a potential migration conduit for either formation water or carbon dioxide.

Effect of an α-lactalbumin-enriched infant formula with lower protein on growth.

BACKGROUND/OBJECTIVES: Protein concentration is lower in human milk (HM) than in infant formula. The objective of this study was to evaluate the effect of an α-lactalbumin-enriched formula with a lower protein concentration on infant growth, protein markers and biochemistries. SUBJECTS/METHODS: Healthy term formula-fed (FF) infants 5-14 days old were randomized in this controlled, double-blind trial to standard formula (SF: 14.1 g/l protein, 662 kcal/l) group (n=112) or experimental formula (EF: 12.8 g/l protein, 662 kcal/l) group (n=112) for 120 days; a HM reference group (n=112) was included. Primary outcome was weight gain (g/day) from D0 to D120. Secondary outcomes included serum albumin, plasma amino acids insulin and incidence of study events. Anthropometric measures were expressed as Z-scores using 2006 World Health Organization growth standards. RESULTS: A total of 321 of the 336 infants (96%) who enrolled, completed the study. Mean age was 9.6 (±2.9) days; 50% were girls. Mean weight gain (g/day) did not significantly differ between SF vs EF (P=0.67) nor between EF vs HM (P=0.11); however weight gain (g/day) was significantly greater in the SF vs HM group (P=0.04). At day 120, mean weight-for-age Z-score (WAZ) and weight-for-length Z-score (WLZ) did not significantly differ between SF vs EF nor EF vs HM; however the WAZ was significantly greater in SF vs HM (P=0.025). Secondary outcomes were within normal ranges for all groups. Incidence of study events did not differ among groups. CONCLUSIONS: α-Lactalbumin-enriched formula containing 12.8 g/l protein was safe and supported age-appropriate growth; weight gain with EF was intermediate between SF and HM groups and resulted in growth similar to HM-fed infants in terms of weight gain, WAZ and WLZ.

Alpha-lactalbumin-rich infant formula fed to healthy term infants in a multicenter study: plasma essential amino acids and gastrointestinal tolerance.

OBJECTIVE: To evaluate the efficacy and safety of an alpha-lactalbumin-enriched formula with a protein profile and total protein concentration closer to human milk (HM) and lower than conventional formulas. SUBJECTS/METHODS: Two hundred and sixteen healthy, term infants,

Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity.

Muscle carnosine synthesis is limited by the availability of beta-alanine. Thirteen male subjects were supplemented with beta-alanine (CarnoSyn) for 4 wks, 8 of these for 10 wks. A biopsy of the vastus lateralis was obtained from 6 of the 8 at 0, 4 and 10 wks. Subjects undertook a cycle capacity test to determine total work done (TWD) at 110% (CCT(110%)) of their maximum power (Wmax). Twelve matched subjects received a placebo. Eleven of these completed the CCT(110%) at 0 and 4 wks, and 8, 10 wks. Muscle biopsies were obtained from 5 of the 8 and one additional subject. Muscle carnosine was significantly increased by +58.8% and +80.1% after 4 and 10 wks beta-alanine supplementation. Carnosine, initially 1.71 times higher in type IIa fibres, increased equally in both type I and IIa fibres. No increase was seen in control subjects. Taurine was unchanged by 10 wks of supplementation. 4 wks beta-alanine supplementation resulted in a significant increase in TWD (+13.0%); with a further +3.2% increase at 10 wks. TWD was unchanged at 4 and 10 wks in the control subjects. The increase in TWD with supplementation followed the increase in muscle carnosine.

Identification and characterization of the Myxococcus xanthus argE gene.

The chromosomal acetylornithine deacetylase (argE) gene of Myxococcus xanthus was identified via homology to acetylornithine deacetylases from other bacterial species. A mutant carrying a disruption in argE was unable to grow on minimal media lacking supplemental arginine and formed fruiting bodies and spores in response to arginine starvation at high cell density.

Cancer mortality following treatment for adult hyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group.

CONTEXT: High-dose iodine 131 is the treatment of choice in the United States for most adults with hyperthyroid disease. Although there is little evidence to link therapeutic (131)I to the development of cancer, its extensive medical use indicates the need for additional evaluation. OBJECTIVE: To evaluate cancer mortality among hyperthyroid patients, particularly after (131)I treatment. DESIGN: A retrospective cohort study. SETTING: Twenty-five clinics in the United States and 1 clinic in England. PATIENTS: A total of 35 593 hyperthyroid patients treated between 1946 and 1964 in the original Cooperative Thyrotoxicosis Therapy Follow-up Study; 91 % had Graves disease, 79% were female, and 65% were treated with (131)I. MAIN OUTCOME MEASURE: Standardized cancer mortality ratios (SMRs) after 3 treatment modalities for hyperthyroidism. RESULTS: Of the study cohort, 50.5% had died by the end of follow-up in December 1990. The total number of cancer deaths was close to that expected based on mortality rates in the general population (2950 vs 2857.6), but there was a small excess of mortality from cancers of the lung, breast, kidney, and thyroid, and a deficit of deaths from cancers of the uterus and the prostate gland. Patients with toxic nodular goiter had an SMR of 1.16 (95% confidence interval [CI], 1.03-1.30). More than 1 year after treatment, an increased risk of cancer mortality was seen among patients treated exclusively with antithyroid drugs (SMR, 1.31; 95% CI, 1.06-1.60). Radioactive iodine was not linked to total cancer deaths (SMR, 1.02; 95% CI, 0.98-1.07) or to any specific cancer with the exception of thyroid cancer (SMR, 3.94; 95% CI, 2.52-5.86). CONCLUSIONS: Neither hyperthyroidism nor (131)I treatment resulted in a significantly increased risk of total cancer mortality. While there was an elevated risk of thyroid cancer mortality following (131)I treatment, in absolute terms the excess number of deaths was small, and the underlying thyroid disease appeared to play a role. Overall, (131)I appears to be a safe therapy for hyperthyroidism.

Effects of varying forage types on milk production responses to whole cottonseed, tallow, and yeast.

Four forage treatments (45% corn silage, 33.75% corn silage plus 11.25% alfalfa hay, 11.25% bermudagrass hay, or 11.25% cottonseed hulls on a DM basis) were arranged factorially with no added fat, 12.5% whole cottonseed, or 2.5% tallow. Different diets were fed during three 28-d periods to 20 control Holstein cows and to 20 cows receiving yeast continuously in a split-plot design. Milk yield of cows fed cottonseed hulls with corn silage was 2.4 kg/d higher than with corn silage plus bermudagrass hay and .7 kg/d higher than with corn silage only or corn silage plus alfalfa hay. Whole cottonseed depressed milk yield by 1 kg/d. Cows fed yeast had increased DMI, and yeast interacted with forage so that more milk was produced by cows fed alfalfa diets. Yeast depressed milk protein percentage. Holstein cows in a commercial Florida dairy were fed no yeast or 10 g/d continuously for 60 d; milk fat percentage was greater (3.51 vs. 3.37%) with yeast. In summary, effects on milk and SCM were positive when cottonseed hulls were utilized with corn silage, negative with whole cottonseed, and neutral with supplemental tallow. Yeast effects on SCM, although not significant for either experiment, tended to be positive for both (mean +1.2 kg/d per cow).

Effects of undegradable protein and supplemental fat on milk yield and composition and physiological responses of cows.

Because some previous studies indicated that addition of dietary fat may delay milk yield response and that effects carry over after withdrawal, an objective of this reversal design with four 28-d periods was to estimate residual effects. Diets were fed 2 wk before period 1 to permit inclusion of pretreatment diet in the mathematical model and changed for each of 33 cows at the start of periods 1 through 3; period 4 treatments continued those for period 3. Diets were 50% corn silage supplemented to be 12% CP with soybean meal and urea; 15% CP with soybean meal, blood and soybean meals, or feather and soybean meals; and 18% CP with soybean meal or blood and soybean meals. Protein treatments were replicated in diets containing 2.0% Ca soaps of fatty acids. No carry-over effects were significant; however, yield increases from Ca soaps were not evident until wk 4. Diet CP had a positive linear effect on milk and SCM yields, BW, and blood urea N. Milk protein percentage was higher from soybean meal diets. Addition of dietary Ca soaps of fatty acids increased milk, protein, fat, and SCM yields. Milk protein percentage was depressed when Ca soaps of fatty acids were fed with blood meal but not with soybean meal. No positive responses were observed from increasing dietary undegradable protein with blood meal or feather meal.

Efficacy of psyllium in reducing serum cholesterol levels in hypercholesterolemic patients on high- or low-fat diets.

OBJECTIVES: To determine the efficacy of psyllium in reducing serum cholesterol levels in patients on high- or low-fat diets. DESIGN: Double-blind, placebo-controlled, 16-week parallel trial. The study included an 8-week baseline period and an 8-week treatment period. PATIENTS: Healthy men and women, 21 to 70 years old, with primary hypercholesterolemia (total serum cholesterol > or = 5.7 mmol/L [220 mg/dL]). Thirty-seven participants followed a high-fat diet and 81 participants followed a low-fat diet. INTERVENTION: Participants were randomly assigned to either psyllium, 5.1 g twice a day, or placebo. MEASUREMENTS: Fasting lipid and apolipoprotein concentrations, including direct low-density lipoprotein (LDL) cholesterol quantification; nutritional analyses of 4 days of 7-day food records to monitor dietary compliance; and physical examinations, clinical chemistry and hematologic studies, and urinalysis to assess treatment safety. MAIN RESULTS: Psyllium recipients in both the high- and low-fat diet groups showed small but significant decreases (P < 0.05) in total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Total cholesterol and LDL cholesterol levels decreased 5.8% and 7.2%, respectively, in psyllium recipients on high-fat diets and 4.2% and 6.4%, respectively, in psyllium recipients on low-fat diets. No significant difference was seen in LDL cholesterol response when psyllium recipients on low- and high-fat diets were compared (P > 0.2). No significant reductions in lipid levels were observed in placebo recipients. Based on the National Cholesterol Education Program LDL cholesterol classification system, 39% of the psyllium recipients improved in LDL cholesterol classification (P < 0.0001) compared with 20.3% of placebo recipients (P > 0.2). CONCLUSIONS: Psyllium produces a modest but significant improvement in total cholesterol and LDL cholesterol levels in persons on either low-fat or high-fat diets. Psyllium, when added to a prescribed low-fat diet, may obviate the need for typical lipid-lowering medications or may prove to be a valuable adjunct to other treatments in patients with moderately elevated LDL cholesterol levels.

Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome.

This study describes the inheritance of a defect in pyrimidine catabolism and its association with drug-induced toxicity in a patient receiving 5-fluorouracil (FUra) as adjuvant chemotherapy for breast carcinoma. The study population included the affected patient (proband), nine of her blood relatives, and seven healthy volunteers. The activity of dihydropyrimidine dehydrogenase (DPD), the initial enzyme of pyrimidine (and FUra) catabolism, in peripheral blood mononuclear cells was measured in each subject by a specific radiometric assay using FUra as the substrate. The proband had no detectable DPD activity. When enzyme levels in the proband and relatives were compared with that in controls, an autosomal recessive pattern of inheritance was demonstrated. This is the third patient with severe FUra toxicity secondary to an alteration in pyrimidine catabolism and the second from our clinic population suggesting that the frequency of this genetic defect may be greater than previously thought. Monitoring DPD activity may be important in the management of patients experiencing severe toxicity secondary to FUra chemotherapy.

Responses of lactating dairy cows to protected fats or whole cottonseed in low or high forage diets.

Thirteen treatments to compare effects of dietary fat on milk yield and composition were control, 15% whole cottonseed, and 2 and 4% Ca-tallowate factorially distributed in low forage (35% corn silage DM) with 14 or 18% CP and high forage (66% corn silage) diets with an additional diet of 8% Ca-tallowate. Different treatments were fed to 36 cows in each of three 28-d periods. Feeding 2 and 4% Ca-tallowate improved milk yield with high forage, although DM intake was slightly depressed; compared with 4% Ca-tallowate, DM intake and milk yield were depressed by 8% Ca-tallowate. Across all diets, whole cottonseed depressed DM intake and milk yield more than when nearly equal fat came from Ca-tallowate (4%). Calcium-tallowate depressed milk fat percentage linearly. Milk fat from cows fed whole cottonseed or Ca-tallowate contained unsaturated fatty acids (mostly C18:1) and lesser quantities of short-chain fatty acids. In a subsequent experiment, Ca-tallowate depressed milk fat percentage, whereas Megalac (calcium salts of fatty acids from palm oil) did not. In a field study, one trial with 210 cows in midlactation showed no effect on milk yield and composition from .54 kg of Megalac/d for 60 d, nor was there any effect detected with 121 cows in early lactation from feeding of .45 kg of Megalac/d for 90 d.

Regional distribution of the expression of a human stimulatory GTP-binding protein alpha-subunit in the human brain studied by in situ hybridization.

Using a cDNA probe complementary to an mRNA coding for the alpha-subunit of a human GTP-binding protein that stimulates adenylate cyclase we have studied its regional distribution in human brain by in situ hybridization histochemistry. The specificity of the hybridization signal was examined by using a labelled sense probe and RNase treatment. Gs alpha transcripts presented a widespread but heterogeneous distribution in human brain postmortem tissues. The cell bodies of the granular layer of the cerebellum were the most heavily labelled cells in all the cases examined. High levels of hybridization were also seen in the pyramidal cell layer of the hippocampus and over the cell bodies of the granule cells of the dentate gyrus. Several cortical regions also presented high levels of hybridization. Another area rich in the Gs alpha mRNA was the hypothalamus. The caudate and putamen nuclei presented intermediate levels while the globus pallidus, the thalamus, the midbrain and the brainstem presented only very low levels of hybridization. This distribution differs from the known distribution of adenylate cyclase activity and other GTP-binding proteins, and could indicate that this particular Gs alpha clone codes for a subset of the alpha-subunit of the Gs protein family.