Pharmacokinetics of oral terbinafine in horses and Greyhound dogs.

The objective of the study was to assess the pharmacokinetics of terbinafine administered orally to horses and Greyhound dogs. A secondary objective was to assess terbinafine metabolites. Six healthy horses and six healthy Greyhound dogs were included in the pharmacokinetic data. The targeted dose of terbinafine was 20 and 30 mg/kg for horses and dogs, respectively. Blood was collected at predetermined intervals for the quantification of terbinafine concentrations with liquid chromatography and mass spectrometry. The half-life (geometric mean) was 8.1 and 8.6 h for horses and Greyhounds, respectively. The mean maximum plasma concentration was 0.31 and 4.01 µg/mL for horses and Greyhounds, respectively. The area under the curve (to infinity) was 1.793 h·µg/mL for horses and 17.253 h·µg/mL for Greyhounds. Adverse effects observed in one study horse included pawing at the ground, curling lips, head shaking, anxiety and circling, but these resolved spontaneously within 30 min of onset. No adverse effects were noted in the dogs. Ions consistent with carboxyterbinafine, n-desmethylterbinafine, hydroxyterbinafine and desmethylhydroxyterbinafine were identified in horse and Greyhound plasma after terbinafine administration. Further studies are needed assessing the safety and efficacy of terbinafine in horses and dogs.

Monocytes contribute to the atherosclerotic cap by transformation into fibrocytes.

AIM: The stability of an atherosclerotic plaque is a key-determining factor in the clinical outcome of cardiovascular disease. In this respect, smooth muscle (SM) alfa actin positive cells play an important role in maintaining plaque stability through formation of a fibrous cap. Recent evidence suggests that circulating progenitors may be a source of these cells. We hypothesized that they may be fibrocytes bone-marrow derived cells that acquire SM-like characteristics, including the expression of SM alfa actin. METHODS: We examined human carotid endarterectomy specimens for the presence of fibrocytes by immunohistochemistry staining for CD34/procollagen I and leukocyte specific protein-1/procollagen I) and examined fibrocyte differentiation in vitro. RESULTS: Fibrocytes were found in regions of plaque growth/healing. They possessed a SM-like spindle shape, produced collagen, and consistent with being fibrocytes they co-localized with transformation growth factor beta, but not serum amyloid P factors, known to promote and inhibit their formation, respectively. While fibrocytes were detected in regions of new growth in 35/40 specimens, only 1/3 of the specimens expressed the SM cell marker calponin, and smoothelin was absent, in these regions. CONCLUSION: Our results demonstrate that fibrocytes contribute to formation of the fibrous cap. With fibrocytes being a monocyte derived cell, we suggest that monocytes may play a more crucial role in the clinical outcome of atherosclerosis than previously realized as they not only contribute directly to plaque instability (through foam cell formation), but also promote plaque stability by transformation into a fibrocyte.

Decreased LRIG1 in fulvestrant-treated luminal breast cancer cells permits ErbB3 upregulation and increased growth.

ErbB3, a member of the ErbB family of receptor tyrosine kinases, is a potent activator of phosphatidyl inositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling, driving tumor cell survival and therapeutic resistance in breast cancers. In luminal breast cancers, ErbB3 upregulation following treatment with the antiestrogen fulvestrant enhances PI3K/mTOR-mediated cell survival. However, the mechanism by which ErbB3 is upregulated in fulvestrant-treated cells is unknown. We found that ErbB3 protein levels and cell surface presentation were increased following fulvestrant treatment, focusing our attention on proteins that regulate ErbB3 at the cell surface, including Nrdp1, NEDD4 and LRIG1. Among these, only LRIG1 correlated positively with ERα, but inversely with ErbB3 in clinical breast cancer data sets. LRIG1, an estrogen-inducible ErbB downregulator, was decreased in a panel of fulvestrant-treated luminal breast cancer cells. Ectopic LRIG1 expression from an estrogen-independent promoter uncoupled LRIG1 from estrogen regulation, thus sustaining LRIG1 and maintaining low ErbB3 levels in fulvestrant-treated cells. An LRIG1 mutant lacking the ErbB3 interaction motif was insufficient to downregulate ErbB3. Importantly, LRIG1 overexpression improved fulvestrant-mediated growth inhibition, whereas cells expressing the LRIG1 mutant were poorly sensitive to fulvestrant, despite effective ERα downregulation. Consistent with these results, LRIG1 expression correlated positively with increased disease-free survival in antiestrogen-treated breast cancer patients. These data suggest that ERα-dependent expression of LRIG1 dampens ErbB3 signaling in luminal breast cancer cells, and by blocking ERα activity with fulvestrant, LRIG1 is decreased thus permitting ErbB3 accumulation, enhanced ErbB3 signaling to cell survival pathways and blunting therapeutic response to fulvestrant.

Improvement in 'stat' laboratory turnaround time. A model continuous quality improvement project.

BACKGROUND: Continuous quality improvement is being advocated as the process that, if adopted, would improve the efficiency, productiveness, and quality of medical institutions, thereby helping to solve the health care crisis our country is facing. To determine if these techniques could be effective in a tertiary-care multispecialty group practice, a model project was undertaken. The model project chosen was to determine if we could improve the turnaround time for "stat" laboratory examinations performed in our large outpatient facility. METHODS: A 10-member team consisting of everyone involved in the process of laboratory testing was empowered to evaluate the present process and make appropriate changes. With traditional techniques of quality improvement, the process was assessed, data were collected and statistically analyzed, changes were introduced, and data were recollected and analyzed. RESULTS: After intervention, the preanalytic delays were reduced by 76% and the postanalytic delays by 88%. Waiting time for patients was reduced by an average of 62%. By instituting the changes suggested, the institution saved $225,000 on a one-time basis and $40,000 to $50,000 on a recurring basis. CONCLUSION: Adoption of quality improvement techniques appears to be a desirable management paradigm that should be explored by all medical institutions interested in maximizing the quality of care offered while at the same time minimizing its cost.

Early regulation of c-myc mRNA by 1,25-dihydroxyvitamin D3 in human myelomonocytic U937 cells.

The effects of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3; 10 nmol/l) on the human monomyelocytic cell line U937 were investigated. Addition of 1,25-(OH)2D3 led to a decrease in cell proliferation which fell at 72 h to 67.8 +/- 4.3% (mean +/- S.E.M.) of control values. The presence of CD14, a surface marker found on mature monocytes/macrophages but not on U937 cells, was detectable as early as 18 h and peaked at 48 h, when 63.6 +/- 4.2% of the cells were positive. However, changes in c-myc mRNA levels were detected earlier, starting within 4 h of exposure to the hormone and being reduced to 38 +/- 8.2% of control values of 24 h. These effects were reversible after removal of the hormone, with the same sequence of events seen following addition of the hormone. There was first an increase in c-myc mRNA levels, starting within 2 h and reaching control values by 24 h. These changes were followed by loss of CD14 which became undetectable after 72 h. Proliferation recovered slowly and incompletely, since it was 81.7 +/- 0.7% of control after 72 h. A constant reciprocal relationship between c-myc mRNA and CD14 levels was found both in the presence and after removal of 1,25-(OH)2D3. Regulation of U937 cell proliferation and maturation by 1,25-(OH)2D3 is thus preceded by early modulation of c-myc mRNA.

Ferredoxin from Aphanothece halophitica, a unicellular blue-green alga: close relationship to ferredoxins from filamentous blue-green algae and phylogenetic implications.

The amino acid sequence of a ferredoxin from a unicellular blue-green alga, Aphanothece halophitica, was established by the conventional methods. Total number of residues was 98 lacking only tryptophan. A most probable phylogenetic tree was constructed for 19 algal ferredoxins on the basis of an amino acid difference matrix made from the sequence comparison. A. halophitica has been classified as a unicellular blue-green alga in the same genus to which Aphanothece sacrum belongs, but the tree indicates A. halophitica ferredoxin to be very close to those of the members of filamentous blue-green algae. The tree divides prokaryotic and eukaryotic algal ferredoxins into several groups, suggesting that the ferredoxin phylogenetic tree reflects the evolutionary trails of various algae, which is also reflected in the structural characteristics, particularly in the presence of gaps. Other notable features are presented in considering algal taxonomy.

Amino acid sequence of Synechocystis 6714 ferredoxin: a unique structural feature of unicellular blue-green algal ferredoxin.

The amino acid sequence of ferredoxin from Synechocystis 6714, a unicellular blue-green alga, was determined by a combination of conventional methods. The ferredoxin was composed of 96 amino acid residues and lacked methionine and tryptophan. The sequence was as follows: Ala-Ser-Tyr-Thr-Val-Lys-Leu-Ile-Thr- Pro-Asp-Gly-Glu-Asn-Ser-Ile-Glu-Cys-Ser-Asp-Asp-Thr-Tyr-Ile-Leu-Asp-Ala-Ala- Glu-Glu-Ala-Gly-Leu-Asp-Leu-Pro-Tyr-Ser-Cys-Arg-Ala-Gly-Ala-Cys-Ser-Thr-Cys- Ala-Gly-Lys-Ile-Thr-Ala-Gly-Ser-Val-Asp-Gln-Ser-Asp-Gln-Ser-Phe-Leu-Asp-Asp- Asp-Gln-Ile-Glu-Ala-Gly-Tyr-Val-Leu-Thr-Cys-Val-Ala-Tyr-Pro-Thr-Ser-Asp-Cys-Thr-Ile-Glu-Thr-His-Lys-Glu-Glu-Asp-Leu-Tyr. In an alignment of various ferredoxins with high homology from unicellular and filamentous blue-green algae, Synechocystis 6714 ferredoxin showed 4 gaps. Those between residues 9 and 10 and between residues 12 and 13 were unique for the ferredoxins from the unicellular algae Synechocystis 6714 and Aphanothece sacrum (ferredoxin I). Therefore, ferredoxins from unicellular algae were distinguishable from those of filamentous algae in terms of the presence of gaps. This feature appears to coincide with the phylogenetic division between the two types of blue-green algae.

A comparison of the effects of two sitting postures on back and referred pain.

This study compared the effects of sitting with portable supports in either a kyphotic or lordotic posture on low-back and referred pain. Two hundred ten patients with low-back and/or referred pain were randomly assigned to either a kyphotic posture or lordotic posture group. The kyphotic and lordotic postures were facilitated by the use of a flat foam cushion or lumbar roll, respectively. Pain location, back pain, and leg pain intensity were assessed over a 24-48-hour period under both standardized clinical settings and general sitting environments. When sitting with a lordotic posture, back and leg pain were significantly reduced and referred pain shifted towards the low back. This study demonstrates that in general sitting environments a lumbar roll results in: 1) reductions in back and leg pain; and 2) centralization of pain. These findings do not apply to patients with stenosis or spondylolisthesis, whose symptoms may be aggravated by use of a lumbar roll.

Systemic effects of topical and subconjunctival ophthalmic atropine in the horse.

OBJECTIVE: To identify any systemic effects of topical and subconjunctival administration of atropine sulfate in the horse. Animals studied Six mature grade horses were treated hourly in one eye with topical ophthalmic atropine drops for 24 h. Five horses were treated subconjunctivally in one eye with 3 mg of atropine sulfate. Procedures Pupillary light reflexes, pupil size, electrocardiographic parameters, girth measurements, intestinal motility, and clinical signs of abdominal pain were monitored. RESULTS: Alteration in auscultated gut motility and clinical signs of abdominal pain were the most sensitive indicators of the systemic manifestations of the topically applied atropine. Gut motility was absent in all horses for periods of 2-18 h in all four abdominal quadrants in horses given topically administered atropine. Signs of abdominal pain were observed in four of six horses that received topical atropine. In the subconjunctival test study, gut motility was absent in three horses for periods of 3-7 h. Uniocular subconjunctival injection of 3 mg atropine sulfate produced signs of abdominal pain in one of six horses. Conclusion The ophthalmic administration of atropine can affect gut motility and induce signs of colic in selected horses.

A new scale for in-home test-weighing for mothers of preterm and high risk infants.

The purposes of this research were to describe the accuracy of test-weighing with the BabyWeigh, a new infant scale suitable for use in the home, and to determine whether mothers and investigators could estimate intake accurately during breastfeeding sessions, using clinical cues that are recommended for this purpose. Within five days of projected NICU discharge, 30 preterm and/or high risk infants and their mothers were studied during a single breastfeeding session. A member of the research team performed test-weights with the Smart Model 20 infant scale, and mothers performed test-weights with the BabyWeigh scale. The mothers and investigators each estimated volume of intake for the breastfeeding session using clinical cues. Mothers and investigators were blind to each others' test-weights and clinical estimates. Results revealed that the BabyWeigh scale provided an accurate estimate of intake during breastfeeding across a large range of infant weights and intake volumes. In contrast, investigator and maternal estimates of intake were not sufficiently accurate.

Subgroup and serotype epidemiology of human rotaviruses recovered at Ga-Rankuwa, southern Africa.

This study analysed human rotaviruses isolated in Ga-Rankuwa, South Africa, using monoclonal antibodies directed at the subgroup-specific and serotype-specific antigens of the virus. The subgroup could be determined for 73pc of the specimens. Subgroup II viruses occurred more commonly than subgroup I viruses (77pc vs 22pc). A serotype specificity could be assigned in 65pc of cases with three serotypes observed to be circulating in this population. Serotype one strains were identified most commonly (43pc) with serotype two (12pc) and serotype four (9pc) strains also present. No serotype three strains were detected. One strain was identified which reacted with both subgroup I and II monoclonal antibodies and with serotype one and two monoclonal antibodies. This study highlights the unpredictable nature of the emergence of new serotypes and importance of surveillance of human rotavirus infection in this sub-continental region.

National training for a new nurse staffing resource management methodology.

The Veterans Affairs (VA) nursing services has implemented a new resource management methodology for determining nurse staffing based on the expert judgment of panels of nurses. This article describes how two educators worked with a development task force to design and implement a national education program to prepare 172 individual health care facility coordinators to implement the methodology. The education program was based on a systems approach emphasizing data collection and analysis, consensus building and expert decision-making. Two pilot programs were conducted and recommendations resulted in a series of 1 1/2-day training sessions conducted across the United States.

A case of congenital central hypoventilation syndrome in a three-generation family with non-polyalanine repeat PHOX2B mutation.

We describe a three generation family in whom multiple individuals are variably affected due to a PHOX2B non-polyalanine repeat mutation. This family demonstrates extreme phenotypic variability and autosomal dominant transmission over three generations not previously reported in the wider literature. Novel findings also inclue a history of recurrent second trimester miscarriage. Pediatr Pulmonol. 2014; 49:E140-E143. © 2014 Wiley Periodicals, Inc.

Prevalence and molecular characterization of pertactin-deficient Bordetella pertussis in the United States.

Pertussis has shown a striking resurgence in the United States, with a return to record numbers of reported cases as last observed in the 1950s. Bordetella pertussis isolates lacking pertactin, a key antigen component of the acellular pertussis vaccine, have been observed, suggesting that B. pertussis is losing pertactin in response to vaccine immunity. Screening of 1,300 isolates from outbreak and surveillance studies (historical isolates collected from 1935 up to 2009, isolates from the 2010 California pertussis outbreak, U.S. isolates from routine surveillance between 2010-2012, and isolates from the 2012 Washington pertussis outbreak) by conventional PCR and later by Western blotting and prn sequencing analyses ultimately identified 306 pertactin-deficient isolates. Of these pertactin-deficient strains, 276 were identified as having an IS481 in the prn gene (prnIS481 positive). The first prnIS481-positive isolate was found in 1994, and the next prnIS481-positive isolates were not detected until 2010. The prevalence of pertactin-deficient isolates increased substantially to more than 50% of collected isolates in 2012. Sequence analysis of pertactin-deficient isolates revealed various types of mutations in the prn gene, including two deletions, single nucleotide substitutions resulting in a stop codon, an inversion in the promoter, and a single nucleotide insertion resulting in a frameshift mutation. All but one mutation type were found in prn2 alleles. CDC 013 was a predominant pulsed-field gel electrophoresis (PFGE) profile in the pertactin-positive isolates (203/994) but was found in only 5% (16/306) of the pertactin-deficient isolates. Interestingly, PFGE profiles CDC 002 and CDC 237 represented 55% (167/306) of the identified pertactin-deficient isolates. These results indicate that there has been a recent dramatic increase in pertactin-deficient B. pertussis isolates throughout the United States.

Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease.

OBJECTIVE: To investigate factors, including cognitive and brain reserve, which may independently predict prevalent and incident dementia of the Alzheimer type (DAT) and to determine whether inclusion of identified factors increases the predictive accuracy of the CSF biomarkers Aß(42), tau, ptau(181), tau/Aß(42), and ptau(181)/Aß(42). METHODS: Logistic regression identified variables that predicted prevalent DAT when considered together with each CSF biomarker in a cross-sectional sample of 201 participants with normal cognition and 46 with DAT. The area under the receiver operating characteristic curve (AUC) from the resulting model was compared with the AUC generated using the biomarker alone. In a second sample with normal cognition at baseline and longitudinal data available (n = 213), Cox proportional hazards models identified variables that predicted incident DAT together with each biomarker, and the models' concordance probability estimate (CPE), which was compared to the CPE generated using the biomarker alone. RESULTS: APOE genotype including an ε4 allele, male gender, and smaller normalized whole brain volumes (nWBV) were cross-sectionally associated with DAT when considered together with every biomarker. In the longitudinal sample (mean follow-up = 3.2 years), 14 participants (6.6%) developed DAT. Older age predicted a faster time to DAT in every model, and greater education predicted a slower time in 4 of 5 models. Inclusion of ancillary variables resulted in better cross-sectional prediction of DAT for all biomarkers (p < 0.0021), and better longitudinal prediction for 4 of 5 biomarkers (p < 0.0022). CONCLUSIONS: The predictive accuracy of CSF biomarkers is improved by including age, education, and nWBV in analyses.

Alzheimer disease identification using amyloid imaging and reserve variables: proof of concept.

OBJECTIVE: Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging. METHODS: Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition. RESULTS: The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73-0.94; cross-validated AUC = 0.80, 95% CI = 0.68-0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90-0.98; cross-validated AUC = 0.91, 95% CI = 0.85-0.96), an improvement (p = 0.025) over that yielded using MCBP alone. CONCLUSION: Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.

Cancer linked to Alzheimer disease but not vascular dementia.

OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.