A longitudinal study of the persistence of increased creatinine and concordance between kidney biomarkers in cats and dogs.

Kidney disease causes morbidity and mortality in dogs and cats. Serum creatinine concentration is an important surrogate marker for glomerular filtration rate (GFR). However, it is not always sensitive to small decreases in kidney function. Efforts to identify additional, more sensitive surrogate markers of GFR to improve detection of early kidney disease has led to the use of symmetrical dimethylarginine (SDMA) in veterinary medicine. There is insufficient information about the behavior of creatinine after an increase and the expected behavior of creatinine and SDMA in these cats and dogs. This study assesses the probability of persistence of increases in creatinine and the subsequent behavior of creatinine and SDMA in animals with persistently increased creatinine. For enrollment, three paired SDMA and creatinine concentrations were required: baseline (T0) with creatinine and SDMA at or below the upper reference limit (URL), T1, and T2 0.5-18 months after T1. The study included 4517 cats and 4576 dogs with increased T1 creatinine concentrations and 54,295 cats and 125,403 dogs with T1 creatinine at or below the URL. The probability of a persistently increased creatinine at T2 was approximately 58% for cats and 49% for dogs after a T1 increase. For animals without a T1 increase the probability of increased creatinine at T2 was only 7% for cats and 3% for dogs. For cats and dogs with persistently increased Cr, the probability of an increased SDMA concentration at T1 was 70-75%. By 24 months, that probability rose to 94% for cats and 88% for dogs.

Longitudinal evaluation of symmetric dimethylarginine and concordance of kidney biomarkers in cats and dogs.

Symmetric dimethylarginine (SDMA) is a sensitive surrogate marker for glomerular filtration rate; however, there are uncertainties as to how to interpret mild increases (SDMA 15-19 µg/dL). This descriptive study used retrospective data to evaluate whether cats or dogs that had initial SDMA values (at T0) within the reference interval followed by an increased SDMA (at T1) had persistently increased SDMA (at T2; measured from 14 days to 18 months following T1; Persistence Cohort), and if and when cats or dogs with persistently increased SDMA had increased creatinine up to 24 months (Concordance Cohort). The Persistence Cohort included 16,670 cats and 16,712 dogs. If SDMA at T1 was 15-19 µg/dL, the probability of persistence was 53% for cats and 42% for dogs, while creatinine was concurrently increased in 20% of cats and 18% of dogs. For comparison, if SDMA was not increased at T1 the probability of increased SDMA at recheck was only 20% for cats and 9% for dogs. For cats and dogs with a T1 SDMA of 15-19 µg/dL and with persistent increases at T2, the probability of increased creatinine at T1 was 20% for cats and 18% for dogs, rising to 61% and 55%, respectively, by 24 months. When SDMA at T1 was >25 µg/dL, creatinine was increased in 93% of cats and 92% of dogs by 24 months. Mildly increased SDMA results may provide an opportunity to identify some cats and dogs earlier in their kidney disease.

Disparities in Opioid Pain Management for Long Bone Fractures.

An expanding body of evidence has established that racial disparities exist in the US healthcare system, manifesting in poorer health outcomes for members of the non-white population. This study examines whether disparities exist in the type of analgesia ordered for long bone fractures and the time to medication administration in a community teaching hospital serving a large Hispanic population. We reviewed de-identified data of 115 patients from the emergency department of a community Level II Trauma Center in central Florida with diagnosed long bone fractures and examined the clinical and demographic variables associated with the type of analgesic administered and factors associated with delays in medication administration. We found that women reported higher pain scores than men, but there was no difference in the type of pain medication administered. There was no difference in pain scores between white and non-white patients; however, white patients were more likely to receive opiates for their long bone fractures compared with non-white patients (70 vs 50%, p < 0.0001). Opioid pain medications were prescribed significantly more often to adult and elderly patients compared with pediatric patients who were more likely to receive acetaminophen compared with both other patient groups (p < 0.001). In summary, we found that pain score was not associated with the class of pain medication administered, but that race and age were. This study questions the utility of the pain score for acute injuries and raises concerns about the role of physician bias in analgesia administration.

Granivory of invasive, naturalized, and native plants in communities differentially susceptible to invasion.

Seed predation is an important biotic filter that can influence abundance and spatial distributions of native species through differential effects on recruitment. This filter may also influence the relative abundance of nonnative plants within habitats and the communities' susceptibility to invasion via differences in granivore identity, abundance, and food preference. We evaluated the effect of postdispersal seed predators on the establishment of invasive, naturalized, and native species within and between adjacent forest and steppe communities of eastern Washington, USA that differ in severity of plant invasion. Seed removal from trays placed within guild-specific exclosures revealed that small mammals were the dominant seed predators in both forest and steppe. Seeds of invasive species (Bromus tectorum, Cirsium arvense) were removed significantly less than the seeds of native (Pseudoroegneria spicata, Balsamorhiza sagittata) and naturalized (Secale cereale, Centaurea cyanus) species. Seed predation limited seedling emergence and establishment in both communities in the absence of competition in a pattern reflecting natural plant abundance: S. cereale was most suppressed, B. tectorum was least suppressed, and P. spicata was suppressed at an intermediate level. Furthermore, seed predation reduced the residual seed bank for all species. Seed mass correlated with seed removal rates in the forest and their subsequent effects on plant recruitment; larger seeds were removed at higher rates than smaller seeds. Our vegetation surveys indicate higher densities and canopy cover of nonnative species occur in the steppe compared with the forest understory, suggesting the steppe may be more susceptible to invasion. Seed predation alone, however, did not result in significant differences in establishment for any species between these communities, presumably due to similar total small-mammal abundance between communities. Consequently, preferential seed predation by small mammals predicts plant establishment for our test species within these communities but not between them. Accumulating evidence suggests that seed predation can be an important biotic filter affecting plant establishment via differences in consumer preferences and abundance with important ramifications for plant invasions and in situ community assembly.

Discovery of novel inhibitors targeting enoyl-acyl carrier protein reductase in Plasmodium falciparum by structure-based virtual screening.

There is a dire need for novel therapeutics to treat the virulent malarial parasite, Plasmodium falciparum. Recently, the X-ray crystal structure of enoyl-acyl carrier protein reductase (ENR) in complex with triclosan has been determined and provides an opportunity for the rational design of novel inhibitors targeting the active site of ENR. Here, we report the discovery of several compounds by virtual screening and their experimental validation as high potency PfENR inhibitors.

Endometriosis of the pancreas presenting as a cystic pancreatic neoplasm with possible metastasis.

The authors report a case of endometriosis that presented as a cystic mass in the tail of the pancreas, leading to extensive evaluation and ultimately a major surgical resection. The diagnosis was made by histopathological evaluation, revealing endometrial glands and stroma in the wall of the mass with hemorrhagic fluid in the cystic lumen, compatible with pancreatic involvement by an endometrial cyst.

Rare systemic dermatologic reaction after pneumococcal vaccine administration.

This case report describes a rare dermatologic reaction in a patient after administration of pneumococcal vaccine. A 65-year-old man developed an extensive dermatitis with pruritus, urticaria, and petechiae 1 week after receiving an intramuscular injection o the vaccine. The reaction resolved with application of topical steroids and oral diphenhydramine hydrochloride. This case report and others in the literature suggest the importance of recognizing the possibility of cutaneous adverse reactions with vaccines, such as the pneumococcal vaccine, which in general have a good safety profile.

Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data.

Tuberculosis and malaria together result in an estimated 5 million deaths annually. The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties. Although genetically unrelated, both organisms use a type II fatty-acid synthase system. Enoyl acyl carrier protein reductase (ENR), a key type II enzyme, has been repeatedly validated as an effective antimicrobial target. Using high throughput inhibitor screens with a combinatorial library, we have identified two novel classes of compounds with activity against the M. tuberculosis and P. falciparum enzyme (referred to as InhA and PfENR, respectively). The crystal structure of InhA complexed with NAD+ and one of the inhibitors was determined to elucidate the mode of binding. Structural analysis of InhA with the broad spectrum antimicrobial triclosan revealed a unique stoichiometry where the enzyme contained either a single triclosan molecule, in a configuration typical of other bacterial ENR:triclosan structures, or harbored two triclosan molecules bound to the active site. Significantly, these compounds do not require activation and are effective against wild-type and drug-resistant strains of M. tuberculosis and P. falciparum. Moreover, they provide broader chemical diversity and elucidate key elements of inhibitor binding to InhA for subsequent chemical optimization.

The TB structural genomics consortium: providing a structural foundation for drug discovery.

Structural genomics, the large-scale determination of protein structures, promises to provide a broad structural foundation for drug discovery. The tuberculosis (TB) Structural Genomics Consortium is devoted to encouraging, coordinating, and facilitating the determination of structures of proteins from Mycobacterium tuberculosis and hopes to determine 400 TB protein structures over 5 years. The Consortium has determined structures of 28 proteins from TB to date. These protein structures are already providing a basis for drug discovery efforts.

Comparison of electrosurgical and formocresol pulpotomy procedures in children.

OBJECTIVES: Although previous studies have examined the electrosurgical pulpotomy technique for primary teeth, no well-controlled, clinical human trials have been published. The purpose of this study was to prospectively compare electrosurgical pulpotomies vs. formocresol pulpotomies in human vital primary molar teeth. DESIGN: Fifty children were randomly divided into two groups, 25 receiving an electrosurgical pulpotomy and 25 receiving a formocresol pulpotomy. RESULTS: After at least 5 months postoperative observation time, the clinical and radiographic success rates for the electrosurgical groups were 96 and 84%, respectively; and for the formocresol group, 100 and 92%, respectively. CONCLUSION: There were no statistically significant differences between the success rates for the two groups at the P < 0.05 level as tested by Fisher's exact test. This study failed to demonstrate a difference in the success rate between the electrosurgical and formocresol pulpotomy techniques.

Management of cutaneous erythrasma.

Corynebacterium minutissimum is the bacteria that leads to cutaneous eruptions of erythrasma and is the most common cause of interdigital foot infections. It is found mostly in occluded intertriginous areas such as the axillae, inframammary areas, interspaces of the toes, intergluteal and crural folds, and is more common in individuals with diabetes mellitus than other clinical patients. This organism can be isolated from a cutaneous site along with a concurrent dermatophyte or Candida albicans infection. The differential diagnosis of erythrasma includes psoriasis, dermatophytosis, candidiasis and intertrigo, and methods for differentiating include Wood's light examination and bacterial and mycological cultures. Erythromycin 250mg four times daily for 14 days is the treatment of choice and other antibacterials include tetracycline and chloramphenicol; however, the use of chloramphenicol is limited by bone marrow suppression potentially leading to neutropenia, agranulocytosis and aplastic anaemia. Further studies are needed but clarithromycin may be an additional drug for use in the future. Where there is therapeutic failure or intertriginous involvement, topical solutions such as clindamycin, Whitfield's ointment, sodium fusidate ointment and antibacterial soaps may be required for both treatment and prophylaxis. Limited studies on the efficacy of these medications exist, however, systemic erythromycin demonstrates cure rates as high as 100%. Compared with tetracyclines, systemic erythromycin has greater efficacy in patients with involvement of the axillae and groin, and similar efficacy for interdigital infections. Whitfield's ointment has equal efficacy to systemic erythromycin in the axillae and groin, but shows greater efficacy in the interdigital areas and is comparable with 2% sodium fusidate ointment for treatment of all areas. Adverse drug effects and potential drug interactions need to be considered. No cost-effectiveness data are available but there are limited data on cost-related treatment issues. A guideline is proposed for the detection, evaluation, treatment and prophylaxis of this cutaneous eruption.

Efficacy of a motilin receptor agonist (ABT-229) for the treatment of gastro-oesophageal reflux disease.

BACKGROUND: ABT-229 is a potent motilin agonist without significant antibiotic activity. It has been shown to improve gastric emptying in humans and to increase lower oesophageal sphincter pressure in cats. AIM: To assess the efficacy of four different doses of ABT-229 (1.25 mg, 2.5 mg, 5 mg, 10 mg b.d.) compared to placebo in the treatment of gastro-oesophageal reflux disease, and to determine its safety in patients with gastro-oesophageal reflux disease. METHODS: In a double-blind, multicentre study, 324 patients with heartburn were randomized to receive four different doses of ABT-229 or placebo for 8 weeks. The efficacy was evaluated by Patient Symptom Questionnaire, daily diary, endoscopy and global evaluation of efficacy. RESULTS: There were no statistically significant improvement scores for any of the ABT-229 treatment groups vs. the placebo group in any of the efficacy parameters. Reflux symptom scores were significantly worse after treatment in the dyspeptic group. ABT-229 appeared to be well tolerated and safe in total daily doses up to 20 mg. CONCLUSION: ABT-229 appears to have limited, if any, clinical utility in the treatment of gastro-oesophageal reflux disease.

Pooled umbilical cord blood as a possible universal donor for marrow reconstitution and use in nuclear accidents.

Human umbilical cord blood has been shown to be an effective source of stem cells for marrow reconstitution in pediatric patients. Unfortunately, the quantity of stem cells obtained from an individual donor can be quite limited in both the total volume and the numbers of stem cells per ml of cord blood. HLA matching further limits the availability, but recent publications indicate close matching may be unnecessary. Therefore, if cord blood from different donors can be combined, larger numbers of stem cells can be available for clinical use provided pooling does not produce a negative effect. Storage of single cord blood specimens at 4 degrees C for 10-21 days in gas permeable bags produced an apparent increase in the percentage of immature cells (CD34, CD117, GPA) and mitotic activity (S+G2/M cells) over day 1. With similar storage of pooled specimens there was a further increase in the number of immature colonies cultured, CD34, CD117, GPA, S+G2/M cells. In addition, nucleated red blood cells increased over the mean values obtained from single cord blood samples. Our previous studies have indicated that large numbers of human mononuclear cells are necessary to reconstitute an irradiated animal model. By combining multiple samples of human cord blood, adequate numbers of stem cells could be pooled for use in adults and would provide cells for megadose therapy, including those patients that had accidentally received lethal irradiation.

Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial.

INTRODUCTION: Erythromycin, a motilin agonist, is a potent prokinetic. ABT-229 is a specific motilin agonist that dose dependently accelerates gastric emptying. Dyspepsia and gastroparesis are common problems in type 1 diabetes mellitus. We aimed to evaluate the efficacy of ABT-229 in symptomatic diabetic patients with and without delayed gastric emptying. METHODS: Patients with type 1 diabetes and postprandial symptoms were randomised (n=270). Based on a validated C(13) octanoic acid breath test, patients were assigned to either the delayed or normal gastric emptying strata. Patients received one of four doses of ABT-229 (1.25, 2.5, 5, or 10 mg twice daily before breakfast and dinner) or placebo for four weeks following a two week baseline. A self report questionnaire measured symptoms on visual analogue scales; the primary outcome was assessment of change in the total upper abdominal symptom severity score (range 0-800 mm) from baseline to the final visit. RESULTS: The treatment arms were similar regarding baseline characteristics. There was symptom improvement on placebo and a similar level of improvement on active therapy for the upper abdominal discomfort severity score (mean change from baseline -169, -101, -155, -143, and -138 mm for placebo, and 1.25, 2.5, 5, and 10 mg ABT-229, respectively, at four weeks by intent to treat). The results were not significantly different in those with and without delayed gastric emptying. The severity of bloating, postprandial nausea, epigastric discomfort, heartburn, and acid regurgitation worsened dose dependently in a greater number of patients receiving ABT-229 than placebo. Overall, 63% of patients on placebo reported a good or excellent global response, and this was not different from the active treatment arms. CONCLUSIONS: The motilin agonist ABT-229 was not efficacious in the relief of postprandial symptoms in diabetes mellitus in the presence or absence of delayed gastric emptying.

The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist.

The 5-HT3 receptor antagonist tropisetron (ICS 205-930) was found to be a potent and selective partial agonist at alpha7 nicotinic receptors. Two other 5-HT3 receptor antagonists, ondansetron and LY-278,584, were found to lack high affinity at the alpha7 nicotinic receptor. Quinuclidine analogues (1 and 2) of tropisetron were also found to be potent and selective partial agonists at alpha7 nicotinic receptors.

Prevalence of CTLA-4 polymorphism A49G in Ashkenazi Jews.

Type 1 diabetes has been associated with numerous genetic loci. One locus, IDD12, includes the gene for cytotoxic T lymphocyte antigen (CTLA-4). A polymorphism at position 49 in the CTLA-4 gene, causing a substitution of Thr --> Ala, has been associated with various autoimmune diseases, including diabetes. The frequency of the polymorphism in European and Oriental populations has been recorded, but the frequency among different ethnic groups within the United States has yet to be established. In the present study, we analyzed 100 DNA samples from Ashkenazi Jews to determine the polymorphism's prevalence in that population. The A/A genotype was found in 49% of individuals, 41% were heterozygous A/G, and 10% possessed the G/G genotype. The prevalence of the A/A genotype in Ashkenazi Jewish population is the highest reported to date. The incidence of the homozygous G/G genotype within Spanish controls, 8.8%, is the lowest, followed by the Ashkenazi general population. The frequency of the non-diabetes-associated A/A genotype shows a similarity to the frequency of the diabetes-susceptible HLA haplotype, DR4-DQ8. The low prevalence of the autoimmune-associated G allele among Ashkenazi Jewish and Spanish populations may explain a lower than expected incidence of diabetes in HLA-susceptible populations.

Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebo-controlled trial.

INTRODUCTION: Motilin-receptor agonists are prokinetics; whether they relieve the symptoms of functional dyspepsia is unknown. We aimed to test the efficacy of the motilin agonist ABT-229 in functional dyspepsia patients with and without delayed gastric emptying. METHODS: Patients were randomized with postprandial symptoms and documented functional dyspepsia by endoscopy (n=589 in intention-to-treat analysis). Patients were assigned to either the delayed or normal gastric emptying strata, based on a validated 13C octanoic acid breath test. Patients were then further randomized within each strata, to receive one of four doses of ABT-229 (1.25, 2. 5, 5 or 10 mg b.d. before breakfast and dinner) or placebo for 4 weeks, following a 2-week baseline. The primary outcome was the assessment of change in symptom severity over the 2 weeks from baseline to final visit, based on a self-report questionnaire measuring severity on visual analogue scales. RESULTS: Baseline characteristics across the treatment arms were very similar. No significant differences in the upper abdominal discomfort severity score (maximum 800 mm) were observed for any active treatment arm vs. placebo (mean change from baseline -139, -141, -145, -160 and -134 mm for placebo, 1.25, 2.5, 5, and 10 mg, respectively, at 4 weeks by intention-to-treat). More patients on placebo reported a good or excellent global response than patients on 1.25 or 5 mg of active therapy (both P < 0.05). The results were very similar in those with and without delayed gastric emptying. Helicobacter pylori status did not predict response. Excluding patients with any baseline heartburn (total remaining n=240), ABT-229 10 mg was inferior to placebo in relief of upper abdominal discomfort. CONCLUSIONS: ABT-229 was of no value for relief of symptoms in functional dyspepsia, compared with placebo.