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OBJECTIVE: Geriatric patients are more sensitive to medications and are at risk for polypharmacy, requiring a medication review. It is hypothesized that a justin-time message to the primary care provider (PCP) recommending a change to potentially inappropriate medications may increase the rate of acceptance of pharmacist recommendations.
DESIGN: Prospective, quality improvement study.
SETTING: Health-system-based primary care facilities.
INTERVENTIONS: Providers were contacted two business days prior to the patient's appointment with a recommendation based on a Beers criteria-derived algorithm. If a PCP was colocated with a pharmacist in the clinic, the preferred method of communication was queried.
PATIENTS, PARTICIPANTS: Medical records of patients 65 years of age or older enrolled in the Johns Hopkins Medicine Alliance for Patients Accountable Care Organization were evaluated for tricyclic antidepressant use in neuropathy, insomnia, and depression; and benzodiazepine use in anxiety and insomnia if prescribed by the PCP.
MAIN OUTCOME MEASURE: The primary outcome was to determine the number of recommendations accepted by the PCP.
RESULTS: A total of 252 recommendations were made with a total of 26.2% recommendations being accepted (22.1% for benzodiazepines and 22.7% for tricyclic antidepressants). Of the 26.2% of recommendations accepted, 56% had a pharmacist in the clinic. A total of 96.7% of PCPs preferred a message to be sent through the patient's medication record.
CONCLUSION: A just-in-time approach in making recommendations to PCPs was successful in leading to medication changes. There was no statistical difference between physician acceptance of pharmacist recommendations in relation to a pharmacist being embedded in the clinic.

Objective: Patient education on high-risk medications such as warfarin is important, and they require quick follow-up after initiation to maximize efficacy and safety. In our Anticoagulation Clinic, two 60-minute new patient appointments are available each day, contributing to prolonged lead-time. We instituted standardized warfarin video education to shorten in-clinic-room visit time, to potentially increase new patient appointments., Methods: Patients viewed the video in the waiting area with a goal to decrease visit times by 15 min (25%), before pharmacists completed their visit. Data collected included time spent in the clinic room, education comprehension, and patient feedback., Results: Ninety patient visits were evaluated in one pre-intervention and two post-intervention phases. Patients who received video education spent less time in the clinic room versus those who had not (52.4 vs 39.4 min, p = 0.001), and two-thirds of all post-intervention visits achieved 25% reduction in visit time. There were no significant differences in education comprehension and patient satisfaction., Conclusion: Video education significantly decreased in-clinic-room visit time, and most patients achieved a goal of 25% reduction in time spent, without a change in comprehension or patient satisfaction., Practice Implications: Implementation of video education can reduce clinic times in many patients without significantly impacting patient satisfaction., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Chronic hepatopathies present a diagnostic challenge, with different diseases being associated with similar clinical and laboratory findings. Characterization of dogs with chronic hepatopathies can be difficult and require costly diagnostic procedures such as acquisition of a liver biopsy specimen. Noninvasive and inexpensive biomarkers that reliably characterize chronic hepatopathies such as chronic hepatitis or a congenital portosystemic vascular anomaly may decrease the need for costly or invasive diagnostic testing and guide novel therapeutic interventions., Objective: To investigate differences in the serum metabolome among healthy dogs, dogs with congenital portosystemic shunts, and dogs with chronic hepatitis., Animals: Stored serum samples from 12 healthy dogs, 10 dogs with congenital portosystemic shunts, and 6 dogs with chronic hepatitis were analyzed., Methods: The serum metabolome was analyzed with an untargeted metabolomics approach using gas chromatography-quadrupole time of flight mass spectrometry., Results: Principal component analysis and heat dendrogram plots of the metabolomics data showed clustering among individuals in each group. Random forest analysis showed differences in the abundance of various metabolites including increased aromatic amino acids and xylitol in dogs with congenital portosystemic shunts. Based on the univariate statistics, 50 metabolites were significantly different among groups., Conclusions and Clinical Importance: The serum metabolome varies among healthy dogs, dogs with congenital portosystemic shunts, and dogs with chronic hepatitis. Statistical analysis identified several metabolites that differentiated healthy dogs from dogs with vascular or parenchymal liver disease. Further targeted assessment of these metabolites is needed to confirm their diagnostic reliability., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

The patient-dentist relationship is a delicate partnership that forms the core of dentistry. The attack on this partnership by the General Dental Council has led to gross miscarriages of justice and the emergence of defensive dentistry. This essay considers the role of a governing body, the misconduct of the GDC and the response of the profession to the injustices perpetrated. The system of NHS general dental practice is considered in terms of quality and humanity and found to be failing in quality and lacking in humanity. The paper concludes that the General Dental Council must go and that NHS general dental practice needs to be terminated. The GDC is apparently not accountable to anyone but the practice of dentistry is accountable to the dentists. The profession will need to be courageous and take action to bring about radical change. A new governing body consisting of young dentists and older more experienced dentists will establish a proper system of professional standards and care for patients. A new, dentist-controlled private system of subsidised general dental practice will be introduced using government financial support for dentistry. The patient-dentist partnership will thus be able to move into a new era of quality and humanity.

Objectives: To compare thawing times of fresh frozen canine plasma between a 37 °C warm water bath, running water bath and dry plasma thawer and compare haemostatic protein stability after thawing in a warm water bath or dry plasma thawer., Materials and Methods: To measure thawing times, a 240-mL bag of frozen plasma was thawed in warm water bath, running water bath or dry plasma thawer-10 times for each method. To evaluate stability of haemostatic proteins, fresh canine donor plasma samples were split into 120-mL bags and 3-mL control aliquots before freezing. Bags were thawed by warm water bath or dry plasma thawer and aliquots equilibrated to room temperature. Concentrations of haemostatic proteins, albumin, D-dimers, prothrombin time and partial thromboplastin time were obtained., Results: The running water bath had the shortest thaw time: median thaw time of 15 minutes versus 18 minutes for both the dry plasma thawer and warm water bath. Statistically significant differences in partial thromboplastin time, factor VII, factor X, von Willebrand factor, and von Willebrand factor collagen binding assay were detected among groups but were unlikely to be clinically relevant., Clinical Significance: A traditional running water bath provided the fastest thawing time but the dry plasma thawer resulted in the most stable haemostatic proteins., (© 2018 British Small Animal Veterinary Association.)

Extreme intestinal polyposis in pet dogs has not yet been reported in literature. We identified a dog patient who developed numerous intestinal polyps, with the severity resembling human classic familial adenomatous polyposis (FAP), except the jejunum-ileum junction being the most polyp-dense. We investigated this dog, in comparison with 22 other dogs with spontaneous intestinal tumors but no severe polyposis, and with numerous published human cancers. We found, not APC mutation, but three other alteration pathways as likely reasons of this canine extreme polyposis. First, somatic truncation mutation W411X of FBXW7, a component of an E3 ubiquitin ligase, over-activates MYC and cell cycle-promoting network, accelerating crypt cell proliferation. Second, genes of protein trafficking and localization are downregulated, likely associated with germline mutation G406D of STAMBPL1, a K63-deubiquitinase, and MYC network activation. This inhibits epithelial apical-basolateral polarity establishment, preventing crypt cell differentiation. Third, Bacteroides uniformis , a commensal gut anaerobe, thrives and expresses abundantly thioredoxin and nitroreductase. These bacterial products could reduce oxidative stress linked to host germline mutation R51X of CYB5RL, a cytochrome b5 reductase homologue, decreasing cell death. Our work emphasizes the close collaboration of alterations across the genome, transcriptome and microbiome in promoting tumorigenesis., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Background: In North America, 250,000 patients on vitamin K antagonists require surgical procedures each year. Temporary interruption of oral anticoagulation and perioperative bridging therapy with unfractionated heparin or low-molecular-weight heparin are recommended by the American College of Chest Physicians 2012 for select patients., Objectives: The study objectives are to evaluate adherence and nonadherence to the Johns Hopkins clinic guidelines for perioperative management of anticoagulation and identify bleeding or thromboembolic events during perioperative management of anticoagulation., Methods: This is a retrospective study of patients who required perioperative management of anticoagulation for an invasive procedure from May 2009 to March 2014. Individualized perioperative anticoagulation management plans were prospectively developed for each patient according to the standardized Johns Hopkins perioperative bridging recommendations and documented in the medical record. Adherence to these standardized Johns Hopkins clinic guidelines, the incidence of thromboembolic events, and bleeding and adverse events during perioperative management were retrieved from the medical record., Results: In 294 perioperative management cases, there was 1 (0.3%) thromboembolism, 3 (1%) major bleeds, and 21 (7%) minor bleeds. One patient experienced facial swelling after starting enoxaparin. There was no difference in thromboembolic (0 vs 1, P = 1.00), major (1 vs 2, P = 1.00), or minor bleeding (14 vs 7, P = 1.00) events in patients managed by providers who were adherent to guidelines when compared with providers who were nonadherent., Conclusion: Our study shows that using a standardized guideline for perioperative management of anticoagulation to inform but not to dictate clinical practice leads to low rates of both thromboembolism and bleeding.

Objectives: To describe the biochemical changes - also known as the storage lesion - that occur in canine packed red blood cells during ex vivo storage., Materials and Methods: Ten 125-mL units of non-leuco-reduced packed red blood cells in citrate phosphate dextrose adenine were obtained from a commercial blood bank within 24 hours of donation. Samples were aseptically collected on days 1, 4, 7, 14, 28, 35 and 42 for measurement of sodium, potassium, chloride, lactate, glucose, pH and ammonia concentrations. All units were cultured on day 42. Friedman's repeated measures test with Dunn's multiple comparison test was used for non-parametric data. A repeated-measures analysis of variance with Tukey's multiple comparison test was used for parametric data. Alpha was set to 0·05., Results: All analytes changed significantly during storage. The mean ammonia on day 1 (58·14 g/dL) was significantly lower (P<0·05) than those on days 28 (1266 g/dL), 35 (1668 g/dL) and 42 (1860 g/dL). A significant increase in median lactate concentration over time was also observed, with day 1 (4·385 mmol/L) being significantly less (P<0·05) than days 14 (19·82 mmol/L), 21 (22·81 mmol/L), 35 (20·31 mmol/L) and 42 (20·81 mmol/L). Median pH was significantly decreased after day 7. All bacterial cultures were negative., Clinical Significance: Many biochemical alterations occur in stored canine packed red blood cells, although further studies are required to determine their clinical importance., (© 2017 British Small Animal Veterinary Association.)

Purpose: The terms population health, population health improvement, and population health management are discussed., Summary: A key concept in defining population health activities is clearly delineating the population(s) of focus. The Institute for Healthcare Improvement's (IHI's) Triple Aim Initiative uses the term population health management to describe the work by healthcare organizations to improve outcomes for individual patients to maximize population health. The National Academy of Medicine favors the term population health improvement and uses this term to describe work to identify and improve aspects of or contributors to population health, expanding the focus beyond traditional healthcare delivery systems. As organizations like IHI and the National Academy of Medicine continue to focus on population health, the terms and definitions used to describe these activities will continue to evolve., Conclusion: The use of consistent, clear definitions for population health activities is critical to the practice of pharmacy and healthcare delivery., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

OBJECTIVE To evaluate the agreement between results of microscopic examination and bacterial culture of bile samples from dogs and cats with hepatobiliary disease for detection of bactibilia. DESIGN Cross-sectional study. ANIMALS 31 dogs and 21 cats with hepatobiliary disease for which subsequent microscopic examination and bacterial culture of bile samples was performed from 2004 through 2014. PROCEDURES Electronic medical records of included dogs and cats were reviewed to extract data regarding diagnosis, antimicrobials administered, and results of microscopic examination and bacterial culture of bile samples. Agreement between these 2 diagnostic tests was assessed by calculation of the Cohen κ value. RESULTS 17 (33%) dogs and cats had bactibilia identified by microscopic examination of bile samples, and 11 (21%) had bactibilia identified via bacterial culture. Agreement between these 2 tests was substantial (percentage agreement [positive and negative results], 85%; κ = 0.62; 95% confidence interval, 0.38 to 0.89) and improved to almost perfect when calculated for only animals that received no antimicrobials within 24 hours prior to sample collection (percentage agreement, 94%; κ = 0.84; 95% confidence interval, 0.61 to 1.00). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that agreement between microscopic examination and bacterial culture of bile samples for detection of bactibilia is optimized when dogs and cats are not receiving antimicrobials at the time of sample collection. Concurrent bacterial culture and microscopic examination of bile samples are recommended for all cats and dogs evaluated for hepatobiliary disease.

Objectives: To describe the clinical outcome of dietary management of Yorkshire terriers with protein-losing enteropathy without immunosuppressive/anti-inflammatory medications., Methods: Records were searched for Yorkshire terriers with hypoalbuminaemia and a clinical diagnosis of protein-losing enteropathy that were managed with diet and without immunosuppressive/anti-inflammatory medications. Serum albumin changes were compared using a one-way repeated measures ANOVA. Canine chronic enteropathy clinical activity index scores were compared using a Wilcoxon signed-rank test., Results: Eleven cases were identified. Clinical signs were variable including: diarrhoea, respiratory signs, vomiting, lethargy and weight loss. Diets fed included home cooked (n=5); Royal Canin Gastrointestinal Low Fat (n=4); Hill's Prescription Diet i/d Low Fat (n=1); or Purina HA Hypoallergenic (n=1). Clinical signs resolved completely in eight dogs, partially resolved in two dogs and failed to respond in one dog. In dogs that responded, albumin significantly improved from baseline (mean 14·9 g/L, sd ±3·7), at 2 to 4 weeks (mean 24·2 g/L, sd ±5·5, P=0·01), and at 3 to 4 months (mean 27·0 g/dL, sd ±5·9, P=0·01)., Clinical Significance: These results indicate that dietary management of protein-losing enteropathy is a potential management strategy in Yorkshire terriers. Randomised clinical trials in Yorkshire terriers with protein-losing enteropathy are necessary to compare success rate, survival and quality of life with dietary management versus combined dietary and immunosuppressive/anti-inflammatory therapy., (© 2017 British Small Animal Veterinary Association.)

Objective: To describe the biochemical changes that occur during storage of feline packed red blood cells., Methods: Feline packed red blood cells were obtained from the manufacturer via overnight delivery immediately following collection. Bag spikes were placed using aseptic technique and samples were drawn on days 1, 4, 7, 14, 21, 28 and 35. Sodium, potassium, chloride, glucose, lactate, pH and ammonia were measured at each time point. Aerobic and anaerobic bacterial cultures were submitted following collection on day 35., Results: There were statistically significant increases in the median concentrations of lactate and ammonia within the first 2 weeks of storage to a concentration of 12·38 mmol/L and 447·96 µmol/L, respectively. Glucose concentrations decreased significantly by day 28 to a mean of 1·86 mmol/L. Median sodium and chloride concentrations increased throughout the course of storage to a concentration of 158·20 and 131·00 mmol/L, respectively. Mean potassium concentrations decreased to a concentration of 2·40 mmol/L., Clinical Significance: These results show that biochemical derangements within feline packed red blood cells are progressive, with some alterations, such as lactate and ammonia, occurring early within the storage periods, while others, including glucose and electrolytes, are slower to develop. Additional prospective research evaluating the clinical effects of these biochemical alterations is required., (© 2016 British Small Animal Veterinary Association.)

Anticoagulation (AC) clinics use the percentage of time in the therapeutic INR range (%TTR) to characterize the quality of management for patients treated with warfarin. In order to guide policy and procedure changes, the purpose of this quality improvement (QI) study was to characterize the AC patient population at The Johns Hopkins Hospital (JHH). We set out to investigate the impact of AC clinic provider continuity on the quality of anticoagulation management. This QI study is a retrospective chart review of 525 warfarin patients managed by pharmacists in the Hematology AC Management Clinic at JHH from June 28, 2013 to November 1, 2014. We recorded patient demographic and clinical characteristics and the quality of AC management using %TTR, and compared these parameters between patients with (Group A) and without a primary AC (Group B). Group A patients had a significantly higher %TTR than Group B patients (53.2 vs. 46.5 %, p = 0.008). In conclusion, we found that patients with a primary AC clinic provider had a higher %TTR than patients with multiple providers. If confirmed prospectively, this approach to warfarin management could represent one technique for AC clinics to optimize patient management and clinical outcomes.

Background: Geolocators are useful for tracking movements of long-distance migrants, but potential negative effects on birds have not been well studied. We tested for effects of geolocators (0.8-2.0 g total, representing 0.1-3.9 % of mean body mass) on 16 species of migratory shorebirds, including five species with 2-4 subspecies each for a total of 23 study taxa. Study species spanned a range of body sizes (26-1091 g) and eight genera, and were tagged at 23 breeding and eight nonbreeding sites. We compared breeding performance and return rates of birds with geolocators to control groups while controlling for potential confounding variables., Results: We detected negative effects of tags for three small-bodied species. Geolocators reduced annual return rates for two of 23 taxa: by 63 % for semipalmated sandpipers and by 43 % for the arcticola subspecies of dunlin. High resighting effort for geolocator birds could have masked additional negative effects. Geolocators were more likely to negatively affect return rates if the total mass of geolocators and color markers was 2.5-5.8 % of body mass than if tags were 0.3-2.3 % of body mass. Carrying a geolocator reduced nest success by 42 % for semipalmated sandpipers and tripled the probability of partial clutch failure in semipalmated and western sandpipers. Geolocators mounted perpendicular to the leg on a flag had stronger negative effects on nest success than geolocators mounted parallel to the leg on a band. However, parallel-band geolocators were more likely to reduce return rates and cause injuries to the leg. No effects of geolocators were found on breeding movements or changes in body mass. Among-site variation in geolocator effect size was high, suggesting that local factors were important., Conclusions: Negative effects of geolocators occurred only for three of the smallest species in our dataset, but were substantial when present. Future studies could mitigate impacts of tags by reducing protruding parts and minimizing use of additional markers. Investigators could maximize recovery of tags by strategically deploying geolocators on males, previously marked individuals, and successful breeders, though targeting subsets of a population could bias the resulting migratory movement data in some species.

Objective: To assess the pharmacokinetic properties of cefovecin in a cold-water teleost species., Animals: 10 healthy adult copper rockfish (Sebastes caurinus), sex unknown., Procedures: Cefovecin (16 mg/kg) was administered SC to the rockfish. Blood samples were collected at predetermined points for measurement of plasma cefovecin concentrations (3 samples/fish). Plasma cefovecin concentrations were measured via liquid chromatography with mass spectrometry. Pharmacokinetic analysis was performed by means of naïve pooled analysis and compartmental modeling. Plasma protein binding of cefovecin was determined by ultrafiltration., Results: Cefovecin administration appeared to be well tolerated by the rockfish. Pharmacokinetic analysis resulted in a maximum plasma concentration of 104.8 μg/mL at 2.07 hours after administration. Plasma terminal half-life was 32.5 hours, and area under the curve was 5,132 h·g/mL. Plasma protein binding was low (< 10%) for plasma concentrations of 10 and 100 μg of cefovecin/mL when assessed at 7.8° and 20°C. Plasma concentrations > 1 μg/mL persisted for the full 7-day follow-up period., Conclusions and Clinical Relevance: SC administration of cefovecin to copper rockfish at a dose of 16 mg/kg yielded plasma concentrations > 1 μg/mL that persisted to 7 days, but some interindividual variability was observed. The low degree of plasma protein binding but high circulating concentration of free drug may allow an extended administration interval in rockfish. Studies are needed to assess the efficacy and safety of this dose in rockfish.

Objective: To determine the impact of processing delay, temperature, and transport tube type on results of quantitative bacterial culture (QBC) of canine urine., Design: Diagnostic test evaluation., Sample: 60 mL of pooled urine from 4 dogs, divided into six 10-mL aliquots., Procedures: Urine aliquots were spiked with bacteria from 1 of 6 independent Escherichia coli cultures to achieve a target bacterial concentration of 10(5) CFUs/mL. One milliliter from each aliquot was transferred into 5 silicone-coated clot tubes (SCTs) and 5 urine transport tubes (UTTs). Samples were stored at 4°C (39°F) and 25°C (77°F) for 0, 8, and 24 hours, and then standard QBCs were performed., Results: Median bacterial concentration for urine samples stored in a UTT for 24 hours at 4°C was lower than that for samples stored in an SCT under the same conditions. Conversely, a substantial decrease in median bacterial concentration was identified for samples stored for 24 hours in an SCT at 25°C, compared with the median concentration for samples stored in a UTT under the same conditions. Median bacterial concentration in samples stored in an SCT at 25°C for 24 hours (275 CFUs/mL) was less than the cutoff typically used to define clinically important bacteriuria by use of urine samples obtained via cystocentesis (ie, > 1,000 CFUs/mL)., Conclusions and Clinical Relevance: Canine urine samples submitted for immediate QBC should be transported in plain sterile tubes such as SCTs. When prolonged (24-hour) storage at room temperature is anticipated, urine samples should be transported in UTTs.

Objective: Adverse drug events are an important cause of admissions to hospitals. Discrepancies in admission and discharge medications can contribute significantly to these adverse events. Patients are at risk of discrepancies in medications any time they experience a transition of care. Medication discrepancies occur more commonly when patients are discharged. Prevention of errors by undergoing medication reconciliation with review by a pharmacist can help avoid medication discrepancy-related errors. The objective of this study was to determine whether integration of pharmacist review in the process of medication reconciliation at discharge identifies and corrects discrepancies., Methods: In the study population of internal medicine patients cared for by hospitalist physicians, we prospectively collected data from medication lists via chart review and patient interview and identified, using a pharmacist, any medication discrepancies. We then counted the number of discrepancies for each patient and categorized them by severity of potential adverse effect to the patient., Results: There were 63 medication discrepancies in 104 included patients found by pharmacist's review and 41% (43) of patients had at least one medication discrepancy. Patients with 8 or more discharge medications were found to be at an increased risk of discrepancy (OR 8.5, p <0.001, 95% CI 2.8,25.5). Most discrepancies were considered minimal risk, 44.4% (28/63), or moderate risk, 49.2% (20/63) for adverse effect., Conclusion: About 2 out of 5 patients on the hospitalist service studied have discrepancies in their medications at discharge that can be identified and corrected by pharmacist intervention. Inclusion of pharmacists could improve the process by correcting these discrepancies to help avoid preventable adverse drug events., (Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Objective: To compare stability of hemostatic proteins in canine fresh-frozen plasma (FFP) thawed with a modified commercial microwave warmer (MCM) or warm water bath (37°C; WWB) or at room temperature (22°C)., Sample: Fresh-frozen plasma obtained from 8 canine donors of a commercial blood bank., Procedures: A commercial microwave warmer was modified with a thermocouple to measure surface temperature of bags containing plasma. The MCM and a WWB were each used to concurrently thaw a 60-mL bag of plasma obtained from the same donor. Two 3-mL control aliquots of FFP from each donor were thawed to room temperature without use of a heating device. Concentrations of hemostatic proteins, albumin, and D-dimers; prothrombin time (PT); and activated partial thromboplastin time (aPTT) were determined for all samples., Results: Significant decreases in concentrations of factors II, IX, X, XI, fibrinogen, von Willebrand factor, antithrombin, protein C, and albumin and significant increases in PT and aPTT were detected for plasma thawed with the MCM, compared with results for samples thawed with the WWB. Concentrations of factors VII, VIII, and XII were not significantly different between plasma thawed with the MCM and WWB. Concentrations of D-dimers were above the reference range for all thawed samples regardless of thawing method. No significant differences in factor concentrations were detected between control and WWB-thawed samples., Conclusions and Clinical Relevance: Significant differences in hemostatic protein concentrations and coagulation times were detected for plasma thawed with an MCM but not between control and WWB-thawed samples. Clinical importance of these changes should be investigated.

Objective: To determine whether dogs with systemic inflammatory response syndrome (SIRS) or sepsis have derangements in serum thyroid hormone concentrations and to evaluate whether such derangements relate to illness severity or outcome., Design: Prospective observational study. Dogs hospitalized with SIRS or sepsis between May and December 2010 were included. Serum thyroid hormone concentrations were measured in all dogs. Data obtained on admission were used to calculate the Acute Patient Physiologic and Laboratory Evaluation (APPLE) scores., Setting: University teaching hospital., Animals: Twenty-two consecutive client-owned dogs hospitalized with SIRS or sepsis were enrolled; 18 dogs completed the study and 4 dogs were excluded for incomplete data. Forty-nine healthy dogs owned by volunteers were used as controls., Interventions: None., Measurements and Main Results: Decreased total thyroxine (TT4) concentrations were documented in all septic and 7/9 dogs with SIRS. Free T4 concentrations were decreased, but were within the reference interval in 12/18 dogs with SIRS or sepsis compared to control dogs (P < 0.001). Dogs with increased APPLE(fast) scores were less likely to survive (P = 0.017)., Conclusions: Dogs with SIRS or sepsis have derangements in measured serum thyroid hormones. No relationships were identified between thyroid hormone concentrations and survival. The APPLE(fast) score was the only variable predictive of poor outcome., (© Veterinary Emergency and Critical Care Society 2014.)

Patients with left ventricular assist devices (LVADs) are at increased risk of bleeding and thrombotic complications making warfarin therapy particularly challenging. Patient self-testing (PST) using point-of-care international normalized ratio (INR) devices has shown favorable outcomes in other populations, but the use of PST in LVAD patients has not been well described. The purpose of this study was to evaluate the effectiveness of pharmacist-managed INR PST versus usual care (UC) in patients with LVADs at a single center. We performed a retrospective cohort study of adult patients (in a 1:4 ratio PST versus UC) implanted with an LVAD (HeartMate II or HVAD) treated with warfarin from January 1, 2007, to January 31, 2013. We reviewed all INRs and bleeding/thrombotic events in LVAD patients whose anticoagulation was managed by clinical pharmacists via INR PST versus UC and calculated a percent time in therapeutic range (%TTR) by Rosendaal method. Fifty-five patients were studied. Demographic data were generally similar between the cohorts. Mean %TTR was higher in the PST cohort versus UC (44.4% vs. 30.6%, p = 0.026). There was no difference in the rate per patient-year of bleeding (0.23 vs. 0.33, p = 0.55) or thrombotic events (0.12 vs. 0.13, p = 0.88). Pharmacist-managed INR PST is associated with an increased %TTR in patients with LVADs.

A theory of rationality is a theory that evaluates instances of reasoning as rational, irrational, or (ir)rational to some degree. Theories can be categorized as rule-based or consequentialist. Rule-based theories say that rational reasoning accords with certain rules (e.g., of logic or probability). Consequentialist theories say that rational reasoning tends to produce good consequences. For instance, the reliabilist takes rationality to be reasoning that tends to produce mostly true beliefs. The pragmatist takes it to be reasoning that tends to produce mostly useful beliefs. This article reviews some of the features and the challenges of rule-based, reliabilist, and pragmatist theories of rationality. WIREs Cogn Sci 2014, 5:27-37. doi: 10.1002/wcs.1263 CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website., (© 2013 John Wiley & Sons, Ltd.)

Objective: To evaluate use of crotalid antivenom, frequency of hypersensitivity reactions, and risk factors for hypersensitivity reactions and death in envenomed cats., Design: Retrospective multicenter case series., Animals: 115 envenomed cats treated with antivenom and 177 envenomed cats treated without antivenom. Procedures-Medical records from 5 institutions were searched by means of a multiple-choice survey with standardized answers for patient data including signalment, diagnosis, antivenom administration criteria, premedication, product, dose, administration rate, hypersensitivity reactions, and mortality rate., Results: 95 of 115 (82.6%) cats received whole IgG antivenom, 11 (9.57%) received F(ab')2 antivenom, and 4 (3.48%) received Fab antivenom. The majority (101/115 [878%]) of cats received 1 vial of antivenom. In all cats, the median dilution of antivenom was 1:60 (range, 1:10 to 1:250) administered over a median period of 2.0 hours (range, 0.3 to 9.0 hours). There was no mortality rate difference between cats that did (6.67%) or did not (5.08%) receive antivenom. A type I hypersensitivity reaction was diagnosed in 26 of 115 (22.6%) cats. The use of premedications did not decrease type I hypersensitivity or improve mortality rate. Cats that had a type I hypersensitivity reaction were 10 times as likely to die as were those that did not have such a reaction., Conclusions and Clinical Relevance: The mortality rate of cats treated with antivenom was low. The administration of premedications did not improve mortality rate or prevent hypersensitivity reactions. The only variable associated with mortality rate was development of a type I hypersensitivity reaction. The rate of antivenom administration should be further evaluated as a possible risk factor for type I hypersensitivity reactions.

Background: A recent genome-wide scan using the canine minimal screening set 2 (MSS-2) showed that cobalamin deficiency appears to be hereditary in Chinese Shar Peis and is linked to the microsatellite markers DTR13.6 and REN13N11 on canine chromosome 13., Objective: The goal of this study was to evaluate the MYC&#95;CANFA gene, which is the closest known gene with a distance of approximately 0.06 megabases (Mb) to the microsatellite marker DTR13.6, for any mutations in this breed., Methods: Microsatellite markers (Myc and G15987) for genotyping and primers for sequencing were used to evaluate the MYC&#95;CANFA gene. The genotype and gene sequence were compared between cobalamin-deficient Shar Peis, Shar Peis with normal serum cobalamin concentrations, and the DNA sequences published as part of the Ensemble Genomic map., Results: Neither the microsatellite markers (Myc and G15987) nor the sequences of the MYC&#95;CANFA gene showed a significant difference among both groups of Shar Peis and the published canine DNA sequence., Conclusions: The data presented here suggest that cobalamin deficiency in Shar Peis is not related to any mutations of the MYC&#95;CANFA gene according to the genotyping and sequencing results in this study. Further investigations are warranted to find a potential genomic locus in proximity to DTR13.6 and REN13N11 that shows mutations in cobalamin-deficient Shar Peis., (© 2012 American Society for Veterinary Clinical Pathology.)

A total of 22,462 serum sample results from dogs being evaluated for gastrointestinal disease at the Gastrointestinal Laboratory, College of Veterinary Medicine, Texas A&M University were evaluated retrospectively. The proportion of dogs with serum cobalamin concentrations below the reference interval and median serum concentrations were compared between Shar Peis and other dog breeds. Serum samples were also obtained prospectively from 22 healthy and 32 Shar Peis with chronic gastrointestinal disease and 59 healthy dogs of other breeds, and serum concentrations of cobalamin, folate, and methylmalonic acid were determined and compared. Overall, 64.0% (89/139) of serum samples from Shar Peis showed serum cobalamin concentrations below the limit of the reference interval and 38.1% (53/139) of these were below the detectable limit for the assay. The median serum cobalamin concentration in Shar Peis was significantly lower than in other breeds. Shar Peis with gastrointestinal disease had significantly lower serum cobalamin and higher serum methylmalonic acid concentrations compared to healthy Shar Peis. Healthy Shar Peis had significantly increased serum methylmalonic acid concentrations compared to healthy dogs of other breeds. There were no meaningful differences in folate concentrations between groups. In conclusion, Shar Peis have a high prevalence of cobalamin deficiency compared to other breeds and healthy Shar Peis may have subclinical cobalamin deficiency., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Due to limited interaction of migratory birds between Eurasia and America, two independent avian influenza virus (AIV) gene pools have evolved. There is evidence of low frequency reassortment between these regions, which has major implications in global AIV dynamics. Indeed, all currently circulating lineages of the PB1 and PA segments in North America are of Eurasian origin. Large-scale analyses of intercontinental reassortment have shown that viruses isolated from Charadriiformes (gulls, terns, and shorebirds) are the major contributor of these outsider events. To clarify the role of gulls in AIV dynamics, specifically in movement of genes between geographic regions, we have sequenced six gull AIV isolated in Alaska and analyzed these along with 142 other available gull virus sequences. Basic investigations of host species and the locations and times of isolation reveal biases in the available sequence information. Despite these biases, our analyses reveal a high frequency of geographic reassortment in gull viruses isolated in America. This intercontinental gene mixing is not found in the viruses isolated from gulls in Eurasia. This study demonstrates that gulls are important as vectors for geographically reassorted viruses, particularly in America, and that more surveillance effort should be placed on this group of birds.

As modern fishery assessments change in an effort to be more accurate and encompass the range of potential ecosystem interactions, critical information on the ecology of species including life history, intra and inter-specific competitive interactions and habitat requirements must be added to the standard fishery-dependent and independent data sets. One species whose movements and habitat associations greatly affects exploitation patterns is lingcod, Ophiodon elongatus, which support an economically important fishery along the coastal waters of the Pacific Coast of North America. High site fidelity and limited movements within nearshore areas are hypothesized to have resulted in high catchability, a major factor that has contributed to overfished stocks. Thus, assessing the level of movement and connectivity among lingcod subpopulations inhabiting nearshore habitats is a prerequisite to determining the condition of lingcod stocks. We used the Pacific Ocean Shelf Tracking (POST) Project acoustic receiver array in Alaska's Prince William Sound to monitor movements and residency of 21 acoustic-tagged lingcod for up to 16 months. Eight of sixteen lingcod (50%) initially aged at 2.5- to 3.5- years-old dispersed from their tag site. Dispersal was highly seasonal, occurring in two, five-week periods from mid-December through January and from mid-April through May. Dispersal in winter may be related to sexually immature lingcod or newly-mature male lingcod being displaced by territorial males. Spring dispersal may be indicative of the onset of migratory behavior where lingcod move out into Prince William Sound and possibly the offshore waters of the Gulf of Alaska. Our results reveal a pattern of ontogenetic dispersal as lingcod approach 4-years-old and exceed 50 cm total length. The large proportion of tagged fish migrating out of Port Gravina, their tagging site, reflects a high level of connectivity among Prince William Sound subpopulations. Our results also support the hypotheses that these subpopulations may be highly susceptible to overfishing because most fish show long residence times.

Loss and/or degradation of nearshore habitats have led to increased efforts to restore or enhance many of these habitats, particularly those that are deemed essential for marine fishes. Copper rockfish (Sebastes caurinus) and lingcod (Ophiodon enlongatus) are dominant members of the typical reef fish community that inhabit rocky and high-relief substrates along the Pacific Northwest. We used acoustic telemetry to document their residency and movements in the nearshore waters of Prince William Sound, Alaska in order to assess use of created reef habitat in an individual-based manner. A total of 57 fish were surgically implanted with acoustic transmitters. Forty-five fish were captured and monitored in three habitats: artificial reef, low-relief natural reef, and patchy high-relief natural reef. Within each habitat, both rockfish and lingcod exhibited long periods of residency with limited movements. Twelve rockfish were captured at the natural reefs and displaced a distance of 4.0 km to the artificial reef. Five of the 12 rockfish returned within 10 d of their release to their initial capture site. Another five of the 12 displaced fish established residency at the artificial reef through the duration of our study. Our results suggest the potential for artificial reefs to provide rockfish habitat in the event of disturbances to natural habitat.

Objective: To evaluate the serine protease inhibitor, Kazal type 1 (SPINK1) gene for variants and to determine their possible association with pancreatitis in Miniature Schnauzers., Animals: 39 Miniature Schnauzers with pancreatitis, 25 healthy Miniature Schnauzers, and 23 healthy dogs of other breeds., Procedures: The entire canine SPINK1 gene with its intron-exon boundaries was initially sequenced in 22 Miniature Schnauzers. Then, 2 regions of the gene were sequenced in 65 additional canine DNA samples at the locations of variants identified in the initial sequencing of the entire SPINK1 gene., Results: Analysis of the SPINK1 gene in Miniature Schnauzers revealed 3 closely associated variants in healthy Miniature Schnauzers and Miniature Schnauzers with pancreatitis. These variants consisted of 2 missense mutations in the second exon (N20K and N25T) and a poly T insertion in the third intron that was near the boundary of exon 3 (IVS3+26-27ins(T)33-39,15&#95;61dup11). Pancreatitis was significantly associated with homozygous alleles for these 3 variants in Miniature Schnauzers. In healthy dogs of other breeds, only the 2 exon variants were identified., Conclusions and Clinical Relevance: Variants of the SPINK1 gene may be associated with the development of pancreatitis in Miniature Schnauzers.

Cardiovascular disease is the leading cause of morbidity and mortality among captive chimpanzees. The most prevalent form of cardiovascular disease among chimpanzees is sudden cardiac death. Myocardial fibrosis was the only significant pathologic lesion observed in affected animals at necropsy. We previously showed an association between myocardial fibrosis and sudden cardiac death. The presumed pathogenesis was interstitial myocardial fibrosis that led to decreased myocardial contractility and interrupted signal propagation in the heart, leading to fibrillation and resulting in sudden cardiac death. In this pilot study, we assayed 5 biomarkers of collagen types I and III metabolism and fibrogenesis and studied their association with CVD in chimpanzees. The biomarker MMP1 did not crossreact in chimpanzee sera and could not be studied further. Two biomarkers (TIMP1 and PINP) and their difference showed no significant association with CVD in chimpanzees. The biomarkers ICTP and PIIINP were significantly increased in cases of CVD with concurrent renal disease. Furthermore, both biomarkers showed a significant trend to increase with disease severity. We conclude that ICTP and PIIINP warrant further study for antemortem detection of renal and myocardial fibrosis in chimpanzees.

Cobalamin deficiency is a common disorder in Chinese Shar Peis (Shar Peis) and is thus suspected to be hereditary. The objective of this study was to identify a genomic region or locus that cosegregates with the phenotype of cobalamin deficiency in Shar Peis. Serum cobalamin concentrations were measured, and blood for genomic DNA extraction was collected from 14 cobalamin-deficient Shar Peis and 28 Shar Peis with a serum cobalamin concentration in the reference range. The 327 microsatellite markers from the canine minimal screening set 2 and 4 additional markers were amplified by polymerase chain reaction and genotyped by automated capillary electrophoresis. Two microsatellite markers, DTR13.6 (P = 1.4 x 10(-6)) and REN13N11 (P = 1.5 x 10(-5)), both on canine chromosome 13, showed evidence of linkage disequilibrium. These findings indicate that the region of chromosome 13 near these markers should be mapped and closely examined for potential mutations associated with this disease in Shar Peis.

We define new measures of sequence similarity for oligonucleotide probe design. These new measures incorporate the nearest neighbor k-stem motifs in their definition, but can be efficiently computed by means of a bit-vector method. They are not as computationally costly as algorithms that predict nearest neighbor hybridization potential. Our new measures for sequence similarity correlate significantly better with nearest neighbor thermodynamic predictions than either BLAST or the standard edit or insertion-deletion defined similarities already in use in many different probe design applications.

DNA nanotechnology often requires collections of oligonucleotides called "DNA free energy gap codes" that do not produce erroneous crosshybridizations in a competitive muliplexing environment. This paper addresses the question of how to design these codes to accomplish a desired amount of work within an acceptable error rate. Using a statistical thermodynamic and probabilistic model of DNA code fidelity and mathematical random coding theory methods, theoretical lower bounds on the size of DNA codes are given. More importantly, DNA code design parameters (e.g., strand number, strand length and sequence composition) needed to achieve experimental goals are identified.

The equation of state of hard hyperspheres in four and five dimensions is calculated from the value of the pair correlation function at contact, as determined by Monte Carlo simulations. These results are compared to equations of state obtained by molecular dynamics and theoretical approaches. In all cases the agreement is excellent.

The purpose of this study was to evaluate the cationic trypsinogen gene in miniature schnauzers for possible mutations. Genetic mutations have been linked with hereditary pancreatitis in humans. Four miniature schnauzers were selected on the basis of a clinical history of pancreatitis. One healthy miniature schnauzer and 1 healthy mixed breed canine were enrolled as controls. DNA was extracted from these canines using a commercial kit. Primers were designed to amplify the entire canine cationic trypsinogen cDNA sequence. A polymerase chain reaction (PCR) was performed and products were purified and sequenced. All sequences were then compared. The healthy control canine, a healthy miniature schnauzer, and the 4 miniature schnauzers with pancreatitis showed identical sequences of the cationic trypsinogen gene to the published sequence. We conclude that, in contrast to humans with hereditary pancreatitis, mutations of the cationic trypsinogen gene do not play a major role in the genesis of pancreatitis in the miniature schnauzer.

The presence of nerves in human tooth pulp has been recognized for over a hundred years, and the innervation of dentine for about 40 years. These observations have been made in permanent teeth. Very few studies have reported on the innervation of the primary pulp and dentine. The purpose of this study was to describe the innervation of the primary tooth pulp-dentine complex. Ten mature primary teeth (one incisor, six canines and three molars) were used. Immediately following extraction they were divided into three sections using a diamond disc and saline coolant. They were then immersion fixed in a solution of formaldehyde and picric acid dissolved in a phosphate buffer pH 7.4). The teeth were then demineralized for 1-3 weeks in formic acid. Following complete demineralization, 30 microns sections were cut on a freezing microtome. Neural tissue was stained using a specific antibody to calcitonin gene related peptide (CGRP). Sections were mounted on glass slides and examined using light microscopy. No individual nerve fibres were seen in the control sections, suggesting that the method used was specific for CGRP-containing nerve fibres. The primary teeth appeared to be well innervated. Myelinated and unmyelinated nerves were seen. There was a dense but variable subodontoblastic plexus of nerves (plexus of Raschkow) and nerve fibres were seen to leave this to travel towards the odontoblast layer. Most terminated here, but a few penetrated the odontoblast layer to enter predentine and the dentine tubules. The maximum penetration was 125 microns but most terminated within 30 microns of the dentinopulpal junction. The coronal region was more densely innervated than the root. Within the crown the cervical third was the most densely innervated region, followed by the pulp horn and the middle third. In conclusion, this study has demonstrated that mature primary tooth contains a pulp which is well innervated and has many nerve endings terminating in or near the odontoblast layer, with a small number penetrating into dentine.

The pulp chambers of 11 freshly extracted human third molars were exposed by cutting off the roots apical to the cervical margin and the pulps were either removed with forceps and discarded or left in situ. The teeth were fixed, demineralized, divided longitudinally, embedded in resin and 2-micron sections stained with toluidine blue were examined by light microscopy. In pulp-removed specimens the percentage retention of the odontoblast layer with the predentine varied near the longitudinal division but when sectioned deeper all six specimens displayed 100% retention. The intactness of the retained odontoblast layer was mostly good as judged by the mutual close apposition of the distal ends of the cell bodies and their relation to the predentine. The retention of the odontoblast layer with the predentine may be due to the distribution of fibronectin, which others have shown is present between odontoblasts, and between odontoblasts and predentine, but lacking beneath the odontoblast layer.

The innervation of pulp and dentine was studied in fully formed human deciduous teeth using antibodies to calcitonin gene related peptide (CGRP). Freshly extracted healthy teeth were divided, fixed, demineralised, cryosectioned and treated with antibodies to human CGRP which was then labelled with horseradish peroxidase. Bundles of nerve fibres passed from the apex of the root to the coronal region where a subodontoblast plexus was formed. In the cervical half of the root some nerve fibres branched away from the main bundles to supply both the odontoblast layer and the dentine. Branches from the coronal subodontoblast plexus also reached the odontoblast layer and the dentine. Most of the nerve fibres terminated in the odontoblast layer. In some areas a marginal plexus of nerves was observed between the odontoblasts and the predentine; intratubular nerve fibres arose either from this plexus or directly from the pulp. The dentine of the crown was more densely innervated than that of the root. In the crown the cervical one third had the most densely innervated dentine followed by the pulp horn and the middle third. The most densely innervated areas occurred in regions where the marginal plexus was present. Although many tubules contained a single nerve filament more complex patterns of termination were also observed. The maximum penetration of a nerve fibre into the dentine was 125 microns. The pattern of the deciduous innervation shows some similarities to the permanent dentition but among the differences is the high density of dentinal innervation in the cervical region. The latter point correlates with the clinical impression of greater sensitivity experienced by patients during invasive procedures performed without anaesthetic in the cervical area.

The pulpal innervation of rabbit premolars and molars has been studied in transverse sections of perfusion-fixed, demineralised specimens using light microscopy and transmission electron microscopy. A mixed population of small myelinated and unmyelinated axons enters the apical foramen to supply the mesial and distal laminae of these continuously growing teeth. The nerve fibres are remote from the preodontoblasts and odontoblasts near the apical end, but in their passage to the occlusal end the pulp becomes progressively narrower and nerve fibres come to lie subjacent to the odontoblasts and postodontoblasts. Counts of myelinated fibres near the apical end and in the occlusal pulp suggested that the myelin is shed near the occlusal end. Most of the dentine in these teeth is tubular and migrates occlusally with supporting odontoblasts. Near the occlusal end, postodontoblasts deposit an atubular tissue which closes the pulpal ends of the tubules. Nearer the occlusal tip the pulpal contents degenerate and become embedded in the forming atubular tissue. Evidence of axon profiles was found near the occlusal end in the pulp, passing through the odontoblast layer and in the dentine tubules adjacent to odontoblast processes. However, many of the tubules contained an odontoblast process only and the atubular tissue was not innervated. Since innervated tubules eventually become closed by atubular tissue it is assumed that the nerve fibres retract from the tubules before their closure. In common with other teeth the function of the pulpal nerve supply is likely to be mostly nociceptive.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: There is growing evidence to suggest the importance of the lymphocyte in the pathogenesis of asthma, particularly in the late phase reactions and ongoing bronchial hyperreactivity. Platelet activating factor (PAF) has also been identified as a potentially important mediator in asthma., Methods: The migration of human peripheral blood lymphocytes obtained from normal volunteers in response to PAF and the effect of PAF antagonists was studied in a well standardised in vitro assay using nitrocellulose micropore filters in a microchemotaxis chamber., Results: PAF is a potent stimulus to in vitro human lymphocyte migration; at an optimal concentration of 1 nM it augmented lymphocyte chemokinesis to 310% (SE 33%) of control values. The response to PAF appears to be specific since lyso-PAF and other related membrane phospholipids had no effect. PAF-induced migration could be abrogated by specific PAF receptor antagonists such as WEB 2086 (100 nM), and was partially blocked by the cyclooxygenase inhibitor flurbiprofen at a concentration of 1 microM., Conclusions: PAF stimulates the in vitro migration of human lymphocytes through a specific PAF receptor. Part of the response may be due to the generation of cyclooxygenase products. PAF may play a part in the recruitment of lymphocytes to asthmatic airways.

Blood smears were examined from 935 individuals of 19 migrant and resident bird species collected in Louisiana. Of these, 320 (34.2%) harbored hematozoa. The prevalences of parasites were as follows: Haemoproteus spp. 22.8%, Trypanosoma spp. 6.9%, unidentified microfilariae 5.0%, Plasmodium spp. 3.4%, and Leucocytozoon spp. 1.3%. These data are consistent with other reports from the region. Infections were observed in 33% of the individuals in the 13 migrant species sampled and 33% of the individuals in the 6 resident species.

Previous experiments in rat incisors indicate that the odontoblasts form an impermeable barrier which prevents fluid movement between pulp and dentine. The permeability of the odontoblast layer has now been investigated in pig molars which are more analogous to human teeth. The heads and necks of anesthetised piglets were perfused intra-arterially with lanthanum nitrate in Ringer's solution or with Ringer's solution alone. Molar tooth germs were removed, sliced, fixed by immersion and embedded in resin. Ultrathin sections including pulp and dentine were examined by transmission electron microscopy. Fenestrated capillaries were permeable to the electron dense lanthanum which thus entered the extracellular space between the odontoblast cell bodies. The lanthanum was excluded from predentine indicating that a barrier to permeability is present. In the above specimens and in others from 2 animals which were fixed by perfusion fixation, longitudinally oriented bundles of collagen fibrils were found passing from dentine through predentine into the odontoblast layer. Longitudinal collagen was also present between odontoblast cell bodies and entering the pulp at their basal ends. This suggests that classical von Korff fibres are present during primary circumpulpal dentinogenesis. In some sections longitudinally oriented collagen was absent. The junctions showed features of classical tight junctions but open tight junctions containing longitudinal collagen were also observed, suggesting that the junctions may modulate. Despite a trace of evidence that lanthanum can leak through adjacent to longitudinally penetrating collagen we concluded that the biological permeability barrier is maintained. The presence of the barrier indicates that other than the longitudinal collagen fibrils of which the source is unknown, all molecules incorporated into dentine are deposited there by the odontoblasts. An advantage of the barrier may be that it provides a closed environment for the orderly process of matrix deposition and mineralisation of dentine.

Fluid movement in the pulp depends largely upon the physiology of the blood vessels; normally there is a net efflux of fluid and proteins from the capillaries into the extracellular environment. Most pulp capillaries lie close to the odontoblast layer and in order to see whether fluid can pass between the odontoblasts into the predentin we have perfused the vessels of molar tooth germs in anesthetized piglets with the electron dense tracer lanthanum. The results show that the tracer permeates the capillaries but encounters a barrier to permeability at the apical (predentinal) ends of the odontoblasts. The completeness of the barrier to the tracer lanthanum is discussed together with structural evidence of tight junctions between odontoblasts in both pigs and humans and the presence of collagen fibers through the tight junctional zone. It is concluded that there is little or no evidence that pulp fluid is normally confluent with predentin. An advantage of this arrangement may be that by maintaining an enclosed microenvironment it permits regulation of the orderly process of matrix deposition and mineralization of predentin to dentin. In order to maintain constant vascular and extracellular fluid pressures the capillary efflux has to be balanced by fluid removal; recent work in cats has shown that lymphatic vessels are available to transport fluid out of the pulp. In this paper the differences in the intrapulpal distribution of these vessels have been extrapolated to human teeth in an attempt to explain certain variations in the symptoms and progress of pulpal inflammatory conditions.

The collagenous fibers of von Korff pass from the dentin matrix between the odontoblasts into the dental pulp. Although collagen fibrils are known to be present between odontoblasts, the existence of von Korff fibers has remained controversial. This may be because their continuity between the dentin matrix and the pulp has not been demonstrated ultrastructurally. In this study we have examined the odontoblast layer in the middle to apical regions of perfusion-fixed permanent canine teeth of cats by using transmission electron microscopy. Ultrathin sections of demineralized specimens revealed frequent bundles of collagen fibrils 1) entering the odontoblast layer from the predentin, 2) present between odontoblast cell bodies, and 3) passing from between the odontoblasts into the pulp. The question of continuity of these bundles from the predentin, across the odontoblast layer into the pulp was examined in ultrathin serial sections. Unbroken continuity of a collagen bundle from the predentin between the odontoblasts into the pulp was established in a reconstruction of one series of 22 serial sections and was very strongly suggested by a number of other series in which the numbers of available sections restricted their full visibility. This investigation has shown, therefore, that classical von Korff fibers are present and that these fibers are present in fully erupted teeth with closed apices, i.e., at a time when secondary circumpulpal dentinogenesis is in progress. The findings call for a reexamination of the question of von Korff fibers during mantle dentinogenesis and primary circumpulpal dentinogenesis. Resolution of their existence at the earlier stages of dentinogenesis should be possible by using the ultrathin serial-sectioning technique.

The existence of lymphatic vessels in the dental pulp has been a matter of continuing controversy. We have now used light microscopy to examine semithin transverse sections of perfusion-fixed incisors and canines in cats. Lymphatics were found in all the teeth studied. In most teeth they were present in the coronal, middle, and apical regions of the pulp; but in a few they were lacking coronally and in the middle. Within individual teeth, lymphatics were found in the subodontoblastic zone or more centrally in the pulp; but none were found in the odontoblast layer or in the pulp horns. Vessels located by light microscopy were subsequently examined by transmission electron microscopy. Their ultrastructural features were typical of lymphatics and included irregular, attenuated endothelium with adjacent cells joined in different ways. Occasional gaps connected the extracellular spaces with their lumens, and abluminal endothelial projections appeared to form open end bulbs. There was very little basement membrane, but anchoring filaments were found near the abluminal surface of the endothelium and near collagen fibrils. The total cross-sectional area of lymphatic vessels was measured in semithin sections and, with pulp area, increased from the coronal region to the middle. However, both areas decreased from the middle to the apical region suggesting either that lymph flows faster as it reaches the foramens of the apical delta or that some vessels leave the tooth through lateral root canals. Using the methods of light and transmission electron microscopy, therefore, we have shown that pulp lymphatic vessels exist. Questions remain, however, about their distribution within teeth, variations between teeth, and routes of exit from teeth.

The fine structure of the tissues immediately adjacent to nerve fibres supplying the rat molar pulp has been examined and compared with that of perineurium of other peripheral nerves. In the periapical region, almost all nerve fibres were invested with typical perineurium; only a few Schwann cell units (unmyelinated axons) lacked perineurium. In the pulp at the apex of the distal root, most fibres were invested by less typical perineurium but some were not invested at all. In the pulp at the coronal end of the root, nerve fibres were completely invested or incompletely invested with attenuated perineurium or lacked investment altogether. In the coronal pulp, there was virtually no perineurium at all. Thus rat molar pulp nerve fibres lack perineurium for distances of about 0.5-3.0 mm, distances greater than in situations such as skin or muscle. In normal peripheral nerves, the perineurium behaves as a barrier to the passage of substances from the immediate environment of the nerve fibres (endoneurium) to the surrounding environment (epineurium) and vice versa. Its absence around pulp nerve fibres raises questions about the nature of the pulp environment and may help to explain the sensitivity of pulp nerves to chemical, osmotic and other stimuli.

Although the rat incisor is used widely in the study of dentinogenesis there is little information on the pulp capillaries and the fate of the pulp contents incisally. The capillaries have now been described in relation to the life cycle of the odontoblasts using light microscopy on perfusion fixed teeth and SEM on pulp vascular casts. Odontoblast precursors differentiated to preodontoblasts in the absence of local vessels. Capillaries entered the zone subjacent to preodontoblasts prior to their transformation to odontoblasts. They invaded the odontoblast layer after formation of odontoblast processes and during lengthening of their cell bodies. These capillaries formed a dense plexus which was separated from the predentine by about 10 micron thickness of odontoblast cytoplasm. Electron microscopy near the incisal end showed that the odontoblasts lost their processes and their polarity to form postodontoblasts. This coincided with the deposition of atubular collagenous tissue at the periphery of the pulp. Loss of fenestrations in the capillaries seemed to coincide with the diminution of odontoblast function. Odontoblastic capillaries were lost before the postodontoblasts became separated from one another. There was evidence of degenerating vessels, cells and extracellular debris near the incisal end. Light and transmission electron microscopical evidence from demineralised teeth was correlated with SEM evidence from anorganically prepared specimens and considered in relation to dynamic events at the incisal surface. Thus the pulp closure region was found to include a central zone of mineralised, moribund pulp cells and debris surrounded by atubular tissue.