Effect of porcine plasma on growth and health of Holstein calves.

The objective of this trial was to compare the health and performance of calves provided high feeding rates of a whey-based all-milk-protein calf milk replacer (MR) with those fed an MR containing either 5% or 10% porcine plasma, which replaced, respectively, either 15% or 30% of the whey-based proteins in the MR formula. A total of 320 male Holstein calves weighing a mean (± SD) of 47.8 ± 4.1 kg were sourced from local dairy farms, auction facilities, and local order buyers. Calves arrived at the research facility in 4 batches of 80 animals each and were randomly assigned to 1 of 3 groups: (1) MR composed of whey-based milk proteins (control group); (2) whey replacement of 5% spray-dried porcine plasma (replacing 15% of protein); or (3) whey replacement of 10% spray-dried porcine plasma (replacing 30% of protein). Calves were housed in individual pens for the first 56 d of the experiment and offered, twice daily, a 26% crude protein (CP), 20% fat MR standardized using synthetic amino acids to 2.4% lysine, 0.8% methionine, and 1.6% threonine. Amounts of MR offered from wk 1 to 8 were 0.65, 0.78, 0.91, 1.04, 1.04, 0.78, 0.52, and 0.325 kg/d, respectively. Calves were also offered a 20% CP texturized calf starter from d 0 to 56 and then transitioned over 7 d (d 56-62) of a 50% calf starter and 50% corn and pellet ration with 2% straw to a corn and pellet ration with 2% straw (18.1% CP) for the remainder of the experiment (d 63-77). Calves were individually weighed upon arrival, weekly through d 56, and at d 77. Grain was fed ad libitum, and remaining grain was weighed weekly to determine weekly consumption. Remaining grain was discarded and was replaced with fresh grain that was weighed and recorded. All milk was offered individually via bucket twice daily, and refusals were recorded following milk feeding by weighing back the remaining unconsumed milk solution. Calves were health scored twice daily, and any medical treatments or mortality were recorded. Time to mortality and medical treatments were analyzed using survival analysis, health scoring data were analyzed using a generalized linear model, and growth was evaluated using a mixed repeated-measures linear regression model. No differences in mortality or incidence of diarrhea were noted between groups. Although there was a high incidence of respiratory disease (65%), no differences were found between groups. Over the entire experimental period, calves gained 67.0 ± 14.9 kg; however, no differences in growth among groups were noted, with the exception that, on d 77, BW was greater for calves in the control group (115.8 ± 15.5 kg) compared with those fed a MR with 5% porcine plasma (113.4 ± 17.8 kg). No differences were found between groups with respect to feed conversion. In this study, an MR composed of either 5% or 10% spray-dried porcine plasma performed comparably to a whey protein-based MR.

Short communication: Effects of different blood buffers administered in electrolyte solution to grain-fed veal calves experiencing diarrhea.

Calf diarrhea can commonly lead to dehydration and metabolic acidosis due to the loss of fluid and electrolytes. The objective of this randomized clinical trial was to examine differences between treating male dairy calves experiencing diarrhea with either a basic bicarbonate electrolyte powder (BBP) composed of sodium bicarbonate (50.7 mmol/L); a mixed buffer powder (MBP) including sodium bicarbonate (33.8 mmol/L), sodium citrate (8.4 mmol/L), sodium acetate (6.3 mmol/L), and potassium citrate (1.9 mmol/L); or a liquid electrolyte (HAL) composed of sodium acetate (50.1 mmol/L). All 3 electrolyte solutions were standardized to provide 50 mmol/L blood buffers and a similarly strong ion difference (74.4, 74.9, and 82.6 mEq/L for BBP, MBP, and HAL, respectively). Holstein male calves (n = 80) were sourced from auction barns or local farms and delivered in 1 batch to the research facility. Calves were housed in individual pens and fed a 24% crude protein and 17% fat calf milk replacer (CMR) twice daily. Starter grain and water were offered ad libitum. Calves were randomly enrolled in 1 of the 3 treatments when experiencing either 2 consecutive days of a fecal score of 2 (runny, spreads easily) or 1 d with a fecal score of 3 (liquid devoid of solid material). Calves were blocked by the different enrollment criteria. The respective electrolyte solution was administered via esophageal tube 1 h after feeding CMR until the fecal score returned to 0 (normal consistency) or 1 (semiformed or pasty). Blood gas measurements were taken at 1, 8, and 24 h post the initial electrolyte feeding, and weight was measured at 1, 2, 7, 14, and 28 d postenrollment. Mixed repeated measure linear regression models were built to assess the effect that the electrolyte solutions had on the blood gas measurements and body weight. A total of 45 calves were enrolled in the trial with 14, 16, and 15 calves randomly assigned to the MBP, HAL, and BBP groups, respectively. As compared with BBP, MBP increased blood CO2 at 8 and 24 h, increased bicarbonate at 24 h, increased base excess at 8 and 24 h, and increased anion gap at 24 h. Calves in the BBP and HAL groups noted more severe eye recession when compared with the MBP group. Average daily gain did not differ between treatments at any time point. Although a severe dehydration challenge was not present, which should be considered a limitation of the study, MBP improved the acid-base status of calves compared with BBP, whereas HAL performed similarly to MBP.

Short communication: Effects of porcine plasma or combined sodium butyrate and Bacillus subtilis on growth and health of grain-fed veal calves.

The objective of this study was to evaluate the effects of incorporating 2 commonly used additives or spray-dried porcine plasma in calf milk replacer (CMR) on calf performance and health. Male Holstein calves (n = 158) transported from auction barns and local dairy farms were randomly assigned to receive 1 of 3 decoquinate-containing CMR for the first 49 d of the experiment: all milk protein and no additives (CONT); 15% of crude protein (CP) replaced with spray-dried porcine plasma, no additives (PLM); or all milk protein and an added combination of sodium butyrate (rate 1.4 kg of butyric acid/Mt) and Bacillus subtilis (1.28 million cfu/g of feed; BB). All milk replacers were formulated to contain 26% CP and 17% fat, 2.4% Lys, and 0.8% Met, and were bucket-fed at daily feeding rates of 520 g during wk 1 and 2, 650 g during wk 3, and 900 g during wk 4 and 5, in a total of 4, 5, and 6 L of solution, respectively. Calves were offered texturized calf starter (18% CP) upon arrival until wk 3 and transitioned to a corn and pellet ration with 2% straw (18.1% CP). No prophylactic administration of antibiotics occurred. All calves were gradually weaned over a 2-wk period. Calves were individually housed until weaned and then housed in groups of 5 in a mechanically ventilated facility in southwestern Ontario, Canada. Fecal scores, treatments administered (antibiotic or supportive therapy), and mortalities were recorded daily. Body weight was measured using a digital scale at arrival and at 14, 49, 56, and 78 d after arrival. No differences were found among the groups with respect to growth, feed efficiency, or incidence of diarrhea or respiratory infection treatment. Calves supplemented with BB had a greater hazard of mortality over the growing period compared with CONT. An interaction was found between the BB group and the level of total serum protein, with the BB group having a lower proportion of days with a fecal score of 3 when the calves had a higher total serum protein level. Calves fed PLM had a lower proportion of d with a fecal score of 3 relative to CONT but no difference in the proportion of d with a fecal score of 2 or higher. This study found that the addition of spray-dried plasma in CMR reduced diarrhea severity; however, supplementing BB was associated with a higher hazard of calf mortality and had a varying response on fecal score.

A survey of enteric bacteria and protozoans in fresh bovine faeces on New Zealand dairy farms.

AIMS: To determine the counts and/or prevalence in fresh bovine faeces of Escherichia coli, enterococci, Campylobacter, Salmonella, shiga toxin-producing E. coli (STEC), Giardia and Cryptosporidium, as inputs to numerical models designed to estimate microbial loadings on pasture grazed by cattle in New Zealand. METHODS AND RESULTS: In each season over one year, samples of freshly deposited bovine faeces were collected from four New Zealand dairy farms (n = 155), and enumerated for E. coli, enterococci, Campylobacter, Giardia and Cryptosporidium. They were also tested for the presence of Salmonella and STEC. The overall median bacterial counts (g(-1) wet weight) were E. coli- 5.9 x 10(6); enterococci - 1.3 x 10(4); Campylobacter- 3.9 x 10(5). All counts were highly variable within and between samplings, and few seasonal or regional patterns emerged. However, mean Campylobacter counts were consistently higher in spring. No Salmonella spp. was detected, and only two samples were positive for STEC. Cryptosporidium and Giardia were isolated from 5.2% and 4.5% of the samples, respectively, yielding low numbers of (oo)cysts (1-25 g(-1) and 1-17 g(-1), respectively). CONCLUSIONS: Fresh bovine faeces are a significant source of E. coli, enterococci and Campylobacter on New Zealand pastures, although numbers are likely to vary markedly between faecal samples. SIGNIFICANCE AND IMPACT OF THE STUDY: The study provides the first significant set of indicator and pathogen counts for one of the largest sources of faecal contamination of natural waters in New Zealand, and will be used to model these inputs.

Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1.

Ultrasound-targeted microbubble destruction (UTMD) was used to direct betacellulin (BTC) and pancreatic duodenal homeobox-1 (PDX1) to rat pancreas 48 h after islet destruction by streptozotocin (STZ). Sprague-Dawley rats were rendered diabetic by STZ injection. Controls included normal rats, STZ only without UTMD, and UTMD with DsRed reporter gene. Blood glucose increased dramatically in all rats 48 h after STZ, and continued to rise after UTMD with BTC alone. Blood glucose declined from day 3 to day 10 after UTMD with PDX1, but remained elevated (261+/-8 mg/dl). However, in rats treated with both BTC and PDX1, blood glucose remained below 200 mg/dl throughout day 10. This was accompanied by normalization of blood insulin and C-peptide. Histology demonstrated islet-like clusters of glucagon-staining cells in the rats treated with BTC and PDX1, but these clusters disappeared by 30 days after UTMD treatment. Although regeneration of insulin-producing islets was not seen, diabetes was reversed for up to 15 days after a single UTMD treatment by ectopic insulin production by pancreatic acinar cells. These cells co-expressed amylase and insulin and demonstrated several beta-cell markers by reverse transcription-PCR. Gene therapy by UTMD can reverse diabetes in vivo in adult rats by restoring pancreatic insulin production.

Effectiveness of ranitidine 150 mg at bedtime as maintenance therapy for healed gastric ulcers.

As many as 89% of gastric ulcer patients experience ulcer recurrences within 1 year of successful healing with conventional antiulcer therapies. Because ranitidine is effective in the healing of gastric and duodenal ulcers and the maintenance of healed duodenal ulcers, we hypothesized that ranitidine would also be effective in the maintenance of healed gastric ulcers. A 48-week, placebo-controlled, randomized, double-blind, multicenter trial was conducted to compare ranitidine 150 mg administered at bedtime with placebo for the maintenance of healed gastric ulcers. Endoscopies were performed at baseline and repeated after 12, 24, 36, and 48 weeks of treatment. Gastric ulcer recurrence rates at each scheduled endoscopy were significantly lower in patients receiving ranitidine (5%, 13%, 16%, and 19%, respectively) compared with those receiving placebo (20%, 30%, 40%, and 50%, respectively). Compared with placebo, ranitidine was more effective in maintaining healed gastric ulcers regardless of previous gastric ulcer history, smoking status, age (< 65 vs > or = 65 years), or sex. There were no significant differences between the two treatment groups in the number of patients experiencing adverse events or laboratory abnormalities. Ranitidine 150 mg administered at bedtime provides safe and effective treatment for the maintenance of healed gastric ulcers.

The gating paradigm: effects of presentation format on spoken word recognition by children and adults.

This study focused on the impact of stimulus presentation format in the gating paradigm with age. Two presentation formats were employed--the standard, successive format and a duration-blocked one, in which gates from word onset were blocked by duration (i.e., gates for the same word were not temporally adjacent). In Experiment 1, the effect of presentation format on adults' recognition was assessed as a function of response format (written vs. oral). In Experiment 2, the effect of presentation format on kindergarteners', first graders', and adults' recognition was assessed with an oral response format only. Performance was typically poorer for the successive format than for the duration-blocked one. The role of response perseveration and negative feedback in producing this effect is considered, as is the effect of word frequency and cohort size on recognition. Although the successive format yields a conservative picture of recognition, presentation format did not have a markedly different effect across the three age levels studied. Thus, the gating paradigm would seem to be an appropriate one for making developmental comparisons of spoken word recognition.

Biochemical characterization of yeast RAS2 mutants reveals a new region of ras protein involved in the interaction with GTPase-activating proteins.

We report biochemical characterization of two recently identified mutants of yeast RAS2, RAS2-E99K and RAS2-E130K. These mutants exhibit dominant activating phenotypes in yeast. Characterization of their intrinsic GTPase and GDP dissociation as well as their ability to stimulate adenylate cyclase showed that these activities of RAS2-E99K mutant protein were similar to those of the wild type protein. RAS2-E130K protein, on the other hand, differed from the wild type protein with a fast GDP dissociation rate and 2-fold higher activation of adenylate cyclase. When the sensitivity to GTPase-activating protein (GAP) was examined, we found that the RAS2-E99K protein was approximately 1200-fold less sensitive to NF1-GAP activity. In addition, the affinity for NF1 as revealed by competition binding experiments was reduced more than 150-fold with RAS2-E99K protein. Thus, the RAS2-E99K mutation affects interaction with GAP proteins. This mutation is particularly interesting because it is the first mutation identified in the alpha 3 region of ras protein that affects GAP interaction. The alpha 3 region appears to be directly involved in interaction with NF1, since peptides containing the sequence encompassing residue 99 of RAS2 inhibit NF1-GAP activity. These results suggest that the interaction between ras and GAP involves a larger region within ras than previously recognized.

A 4-week, multicenter, duodenal ulcer healing trial comparing four escalating doses of ranitidine.

In a randomized double-blind 4-wk trial, ranitidine doses of 300 mg at bedtime (hs), twice daily (bid), three times daily (tid), and four times daily (qid) were compared in 629 patients with endoscopically confirmed duodenal ulcer(s). Endoscopies were performed at baseline and after 4 wk of therapy. Per protocol analysis revealed wk 4 healing rates that were significantly increased (p < or = 0.001) for the bid, tid, and qid groups, compared with the hs group. All treatments provided early symptomatic (ulcer pain) relief. No significant differences in adverse events or laboratory abnormalities were observed between groups. Ranitidine 300 mg bid provides an alternative therapeutic approach for patient populations at risk for ulcer complications. These patients include those with the following: a past history of an upper gastrointestinal hemorrhage, perforation, obstruction, penetration, or giant (> 2.0 cm) duodenal ulcer. The elderly and those with chronic unresponsive ulcerations may also be included in this population.

University Hospitals Association: 'the registrar problem'.

Registrars form a heterogeneous group of doctors with different functions. The difficulties in forecasting and recruiting the correct number of doctors to the grade and the problems of reforming their training and of creating an improved career structure were discussed at a meeting of the University Hospitals Association.

A dominant activating mutation in the effector region of RAS abolishes IRA2 sensitivity.

Previously described mutations in RAS genes that cause a dominant activated phenotype affect the intrinsic biochemical properties of RAS proteins, either decreasing the intrinsic GTPase or reducing the affinity for guanine nucleotides. In this report, we describe a novel activating mutation in the RAS2 gene of Saccharomyces cerevisiae that does not alter intrinsic biochemical properties of the mutant RAS2 protein. Rather, this mutation, RAS2-P41S (proline 41 to serine), which lies in the effector region of RAS, is shown to abolish the ability of the IRA2 protein to stimulate the GTPase activity of the mutant RAS protein. This mutation also modestly reduced the ability of the mutant protein to stimulate the target adenylate cyclase in an in vitro assay, although in vivo the phenotypes it induced suggest that it retains potency in stimulation of adenylate cyclase. Our results demonstrate that although the effector region of RAS appears to be important for interaction with both target effector and negative regulators of RAS, it is possible to eliminate negative regulator responsiveness and retain potency in effector stimulation.

IRA2, an upstream negative regulator of RAS in yeast, is a RAS GTPase-activating protein.

The ras GTPase-activating protein (GAP), identified and characterized in mammalian cells, stimulates the intrinsic GTPase activity of ras proteins. We have previously proposed that the IRA genes, negative regulators of RAS genes in Saccharomyces cerevisiae, encode yeast homologs of the mammalian GAP. In this paper, we present the following evidence that a product of the IRA2 gene exhibits GAP activity similar to that of the mammalian GAP protein. (i) Extracts of yeast cells overexpressing IRA2 stimulated the GTPase activity of the yeast RAS2 protein. (ii) An epitope for a monoclonal antibody (12CA5) was added to the N terminus of the IRA2 protein. The GAP activity of extracts prepared from cells expressing this fusion protein was shown to be immunoprecipitable by 12CA5. (iii) An IRA2 protein fused to glutathione S-transferase (GST) was produced and partially purified from Escherichia coli cells. GAP activity was detected with this purified GST-IRA2 fusion protein. (iv) The GAP activity of IRA2 proteins described above did not stimulate the GTPase activity of the RAS2Val19 protein, a protein having an amino acid alteration analogous to that found in mammalian oncogenic ras proteins. This result parallels studies showing that mammalian GAP is incapable of stimulating the GTPase activity of mammalian oncogenic proteins. The remarkable conservation between the GAP activity in mammalian and yeast cells supports the idea that the function of GAP is to negatively regulate ras proteins in mammalian cells.

Effect of an upper-arm constricting device on arm blood pressure measurements.

Thousands of blood pressure measurements are done daily without the patients' disrobing. This study was therefore undertaken to determine the validity of such measurements, especially those taken when the patient's armsleeve has been rolled up onto the proximal aspect of the arm. An inflatable constricting device was applied to the proximal aspect of the arm and a standard sphygmomanometer was applied distal to the inflatable cuff. The constricting cuff was inflated to 0, 20, 40, 60, 80, and 100 mm Hg in random sequence, and the blood pressure was recorded at each level. Statistically significant elevations in the mean systolic blood pressure were detected at proximal constricting pressures of 80 mm Hg (P less than .01) and 100 mm Hg (P less than .001), and in the mean diastolic blood pressure at 20 mm Hg (P less than .005). However, the magnitude of the elevations was small: 3.9, 4.4, and 2.5 mm Hg, respectively. We conclude that though a proximal constricting device may induce statistically significant alterations in blood pressure measurements these alterations are small and not likely to affect treatment decisions.

Arbaprostil's [15(R)-15-methyl PGE2] effects on intrauterine pressure in the nonpregnant and pregnant human female--a report of four clinical trials.

Four clinical trials evaluating arbaprostil's effects on the human uterus are reported. The initial two trials measured intrauterine pressures in nonpregnant and pregnant human females following arbaprostil doses of 10, 25, and/or 50 mcg. No statistical differences were found at any dosage level in either study for average uterine resting pressures, average peak pressures, the number of contractions or Montevideo units. Subsequently, two trials determined the abortifacient potential of arbaprostil in pregnant women during the first trimester. The first utilized total daily doses of 400 and 800 mcgs. while the second used total daily doses of 1200 and 1600 mcgs. Vaginal spotting was noted in one woman receiving 400 mcgs, three receiving 1200 mcgs. and in two receiving 1600 mcgs. One episode of moderate bleeding was seen in the latter study. Based on these studies, arbaprostil exhibits little potential for inducing abortifacient activity at these dosages in these patient populations.

Azelastine inhibits stimulated histamine release from human lung tissue in vitro but does not alter cyclic nucleotide content.

To investigate the mechanism by which azelastine may be effective therapeutically in asthma, we studied its ability to inhibit anti-IgE- and calcium ionophore A23187-stimulated histamine release from human lung and to alter lung cyclic nucleotide levels. Significant inhibition of histamine release from both anti-IgE- and A23187-stimulated human tissue was apparent after 30 minutes preincubation of the lung tissue in azelastine. Significant inhibition of anti-IgE-stimulated histamine release was consistently seen in azelastine concentrations greater than or equal to 5 microM, and was dose dependent (r = 0.71, p less than 0.05) with maximal mean inhibition of 53 +/- 11%. For A23187-stimulated lung tissue, consistent inhibition of histamine release was not found until we used 30 microM azelastine, mean 35 +/- 11%. Inhibition in azelastine concentrations below 30 microM was variable and not significant. Lung cyclic AMP and cyclic GMP content was not significantly altered by incubation of lung tissue in 100 microM azelastine. We conclude that azelastine inhibits stimulated histamine release from human lung tissue in vitro but does not alter cyclic nucleotide content.

Arbaprostil [15(R)-15-methyl prostaglandin E2] in a single nighttime dose of either 50 or 100 micrograms in acute duodenal ulcer.

To determine the efficacy of single nighttime doses of arbaprostil [15(R)-15-methyl prostaglandin E2], 50 or 100 micrograms for 4 wk, a double-blind randomized placebo-controlled multiclinic trial was undertaken. Success was defined as complete healing of the ulcer documented by endoscopy. Fifty-one of 64 patients enrolled were considered evaluable. Ulcer healing was documented in 64.3%, 85.7%, and 31.2% of the 100-micrograms arbaprostil, 50-micrograms arbaprostil, and placebo treatment groups (p value vs. placebo = 0.003 and 0.002, respectively). No difference in side effects or changes in laboratory parameters were found between the treatment groups except that diarrhea, usually mild, was found more often in the 100-micrograms arbaprostil group (60.0%) than in the 50-micrograms arbaprostil (31.8%) or placebo groups (23.5%) (p value 100 micrograms arbaprostil vs. placebo = 0.02). A single nighttime administration of arbaprostil seems to be a safe and efficacious agent for the treatment of acute duodenal ulcer.

Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome.

Although fatigue is one of the most common complaints in ambulatory care, research has been minimal. Of the 1159 consecutive patients surveyed in two adult primary-care clinics, 276 (24%) indicated that fatigue was a major problem. Fatigue was more prevalent in women than in men (28% vs 19%). Extensive clinical, laboratory, psychometric, and functional data were gathered for 102 fatigued patients and 26 controls. Laboratory testing was not useful in detecting unsuspected medical conditions or in determining the cause of fatigue. Depression or somatic anxiety or both were suggested by screening psychometric instruments in 82 fatigued patients (80%) compared with three controls (12%). Global dysfunction was marked, as reported by patients on the Sickness Impact Profile. The mean score on the Sickness Impact Profile of 11.3 for fatigued patients is similar to that reported for patients with major medical illnesses. After one year of follow-up, only 29 fatigued patients (28%) had improved. The high prevalence, persistence, and functional consequences of fatigue mandate a search for effective therapy.

Fluoxetine, a selective serotonin uptake inhibitor, for the treatment of outpatients with major depression.

In a double-blind, placebo-controlled study the authors found that fluoxetine, a potent and selective inhibitor of serotonin reuptake, was an effective antidepressant in moderately depressed, ambulatory outpatients. Typical adverse effects reported by patients treated with fluoxetine included agitation, nausea, fatigue, and insomnia. Compared to imipramine, fluoxetine was associated with fewer complaints of dry mouth, constipation, and dizziness.