Clarifying dairy calf mortality phenotypes through postmortem analysis.

Health problems can be thought of as phenotypic expressions of the complex relationships between genes, environments, and phenomes as a whole. Detailed evaluations of phenotypic expressions of illness are required to characterize important biological outcomes. We hypothesized that classifying dairy calf mortality phenotypes via a systematic postmortem analysis would identify different cause-of-death diagnoses than those derived from treatments alone. This cross-sectional study was carried out on a dairy calf ranch in the northwestern United States from June to September 2017 and focused on calves ≤90 d of age. Comparisons were made between causes of death based on 3 levels of information: on-farm treatment records alone, necropsy-based postmortem analyses in addition to treatment records, and Washington Animal Disease Diagnostic Laboratory (WADDL) results in addition to all other information. A total of 210 dairy calves were necropsied during this study, of which 122 cases were submitted to WADDL. Necropsy- and WADDL-derived mortality phenotypes were in almost perfect agreement (Cohen's κ = 0.86) when broadly categorized as diarrhea, respiratory, diarrhea and respiratory combined, or other causes. The level of agreement between on-farm treatment records and postmortem-derived results was low and varied by the level of diagnostic detail provided. There was just fair agreement (κ = 0.22) between treatment-based and necropsy-based phenotypes without WADDL input and only slight agreement (κ = 0.13) between treatment-based and corresponding necropsy-based phenotypes with WADDL input. Even for those cases in which causes of death aligned along a comparable pathologic spectrum, the lack of detail inherent to standard treatment-based causes of death failed to identify meaningful target areas for intervention. This was especially apparent for numerous cases of necrotizing enteritis and typhlitis (cecal inflammation) that were variously categorized as diarrhea and pneumonia by treatment-based diagnoses. The specificity of these lesions stood in stark contrast to the otherwise generic cause of death diagnoses derived from treatments. The findings from this study supported the hypothesis and highlighted the value of on-farm necropsies and laboratory-based diagnostics to (1) detect antemortem disease misclassifications, (2) provide detail regarding disease processes and mortality phenotypes, and (3) direct disease mitigation strategies.

Adjunctive pregabalin for uncontrolled partial-onset seizures: findings from a prospective audit.

AIMS: Pregabalin (PGB) was licensed in Europe as an add-on antiepileptic drug (AED) for the treatment of partial-onset seizures in 2004. This audit assessed the response to adjunctive PGB in patients with uncontrolled seizures. METHODS: PGB was titrated in 135 patients [73 men; 62 women, aged 18-76 (median 44 years) until one of the following occurred: ≥ 6 months' seizure freedom, ≥ 50% or < 50% seizure reduction over 6 months; PGB withdrawal because of adverse effects, lack of efficacy or both. RESULTS: Of the 135 patients, 14 (10.4%) became seizure-free for ≥ 6 months (median PGB dose 300 mg/day; range 75-600 mg). A ≥ 50% seizure reduction occurred in 33 (24.4%) patients; 20 (14.8%) had < 50% reduction. PGB was withdrawn in 68 (50.4%) (40 adverse effects, seven lack of efficacy and 21 both). Commonest problems resulting in withdrawal were sedation (n = 18), weight gain (n = 14) and ataxia (n = 9). There was a positive correlation between increasing dose and weight gain (r = 0.42, P = 0.045). CONCLUSIONS: Add-on PGB benefited 50% of patients, but only 10% achieved 6 months' seizure freedom. Adverse effects, most commonly sedation, dose-related weight gain and ataxia, led to drug discontinuation by 45%. Prospective audits of novel AEDs are a useful adjunct to randomized, controlled trials in managing epilepsy.

Feline systemic reactive angioendotheliomatosis: eight cases and literature review.

A rare, multisystemic intravascular proliferative disorder was identified postmortem in eight cats. The majority of these cats died or were euthanized following episodes of dyspnea, lethargy, and anorexia. Microscopic examination revealed occlusive, intraluminal proliferations of spindle cells within small vessels. The heart was consistently involved, and myocardial dysfunction was the probable cause of illness in all cats. Immunohistochemically, the majority of intravascular cells expressed von Willebrand factor, and a smaller number expressed smooth muscle actin, compatible with a dual population of endothelial cells and pericytes, suggesting a reactive rather than a neoplastic process. Four cases of a similar feline vascular disorder from the veterinary literature are reviewed. The histopathology resembles reactive angioendotheliomatosis in humans, a benign cutaneous intravascular endothelial and pericytic proliferative condition. However, in contrast, this feline disease is multisystemic and fatal. We propose the name "feline systemic reactive angioendotheliomatosis" for this unique, idiopathic disorder of domestic cats.

Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response.

PURPOSE: In spite of rapidly growing interest, few research tools have been developed to study female sexual dysfunction. Using the D(1)/D(2) agonist, apomorphine (APO), our objective was to develop a new model of the sexual arousal response in female rats based on one previously established for the male condition. METHODS: APO (80 micro g/kg, s.c.) was given during proestrus (P), estrus (E), metestrus (M), early diestrus (DI) and late diestrus (DII), and in ovariectomized (OVX) female Wistar rats. APO-induced behavioral and genital responses were characterized (30 min) using video monitoring. RESULTS: APO-induced reproducible, periodic morphological changes in the external genitalia. The onset, timing and duration of these female APO responses were consistent with genital vasocongestive arousal (GVA) responses in males (ie erections). APO-induced GVAs occurred throughout the estrous cycle, peaking in E (1.4+/-1.21 overall; 0.9+/-0.64 in DII; 1.8+/-1.66 in E) and were markedly diminished by ovariectomy (OVX, 0.4+/-0.51). CONCLUSION: APO induced a reproducible sexual arousal response in female rats involving obvious genital vasocongestive engorgement. Further, the findings demonstrate that the APO-induced genital arousal responses are hormonally regulated.

Stewardship or clinical freedom? variations in dialysis decision making.

BACKGROUND: It is generally agreed that acceptance criteria for dialysis have varied and changed over time and that implicit rationing, to some extent forced on clinicians by limited capacity, has been widely practised. Our objective was to study the basis and extent of variation in dialysis decision making among nephrologists in one NHS region. DESIGN AND METHODS: In a clinical judgement analysis, linear regression models were employed to reflect the impact of clinical and non-clinical cues on nephrologists' decisions to offer dialysis to 60 'paper patients' under current capacity constraints and under an assumption of no capacity limit. A short questionnaire was also completed by eight nephrologists to elicit their expressed decision drivers, which were subsequently compared with those tacitly derived from the appraisal of the 60 clinical vignettes. RESULTS: Doctors showed substantial variation in their propensity to offer dialysis and in their perceptions of the benefits of dialysis. Even for the five patients where the discordance in propensity to offer dialysis was least, the range in perceived gain in life expectancy was from 24 to 264 months (mean 91 months). The decision models had relatively good explanatory power with an average r(2) of 0.67 (0.39-0.90) and 0.70 (0.47-0.95) for decisions made under current capacity constraints and under an assumption of no limit capacity respectively. Surprisingly, for most doctors, the patient's age had very little impact on dialysis decisions but the magnitude of the beta-coefficients for the patient's mental state (mean -30.7) was of a similar order of magnitude to the coefficient for the principal 'renal' drivers (e.g. the mean coefficient for uraemic symptomatology under current capacity constraints was 47.7). The influence of other non-renal factors on the doctor's likelihood to offer dialysis was largely independent of the capacity assumption. A comparison of the doctor's stated decision drivers with those tacitly derived from their decision models showed only modest correlation. CONCLUSIONS: The extent to which doctors vary in their propensity to offer dialysis is substantial. Very few non-clinical cues appear to influence the decision to offer dialysis. The most important non-renal factor in determining dialysis decisions was the patient's mental state.

Revising appointment, promotion, and tenure procedures to incorporate an expanded definition of scholarship: the University of Kentucky College of Medicine experience.

Scholarly activity and scholarly productivity are key features of the academic health center (AHC) and the work of college of medicine faculty. Recent changes in the academic environment of the University of Kentucky (UK) College of Medicine led to an examination of its appointment, promotion, and tenure procedures. This, in turn, led to a re-examination of the college's definition of scholarship. This article describes three of UK's scholarship-related challenges, particularly those related to clinical departments. The authors describe some of the new procedures being implemented to address these challenges; these include new faculty designations, clearer articulation of promotion procedures, explicit recognition of multiple forms of scholarship, expectations for investment in junior faculty, and mandatory discussion of faculty success in chairs' annual reviews. Faculty reactions, positive and negative, to these changes in procedures are also presented.

High dose gabapentin in refractory partial epilepsy: clinical observations in 50 patients.

Fifty patients with refractory partial seizures took part in a prospective, observational study of adjuvant gabapentin (GBP) in increasing doses. Thirty-three were started on 400 mg GBP daily with further weekly increments of 400 mg until seizures came under control for at least 6 months or to the limit of tolerability. A further 17 patients, not fully controlled on low dose GBP, followed the same regimen. All patients took the drug three times daily. Comparisons were made with seizure numbers during a 3-month baseline during which antiepileptic medication remained unchanged. Overall, 24 of the 50 patients documented a seizure reduction of 50% or more. Fifteen did so at or below 2400 mg GBP daily. Three of these patients became seizure-free. The remaining nine appeared to respond to higher daily doses of GBP (1:2800 mg; 3:3600 mg; 1:4000 mg; 1:4800 mg; 3:6000 mg), with two becoming seizure-free. Side-effects most commonly reported included tiredness, dizziness, headache and diplopia. On GBP doses exceeding 3600 mg daily, three patients developed flatulence and diarrhoea and two more had myoclonic jerks. Mean circulating GBP concentrations (mg/l) at each 1200 mg dose level were as follows: 1200 mg-4.1; 2400 mg-8.6; 3600 mg 13.2; 4800 mg 15.5; 6000 mg-17.2. In six patients, including three taking 6000 mg daily, GBP concentrations continued to rise linearly at each dosage increment. Although limited, our results do not support the suggestion that GBP absorption is saturable. High dose GBP may be effective in controlling seizures in patients with refractory partial epilepsy.

Multiple options and unique pathways: a new direction for EMS?

The same forces transforming the health care delivery system also are reshaping EMS. The changing economic and organizational structures of the health services delivery system may predict how EMS systems will redesign themselves. We discuss one template for future EMS systems.

The Kentucky medical curriculum. A response to the call for educational reform: a GPEP report card.

The resources of an important educational grant provided by the Robert Wood Johnson Foundation, as well as designated local college and medical center funds, provided support for the renewal of the undergraduate medical education program at the University of Kentucky College of Medicine. The fully revised medical curriculum, adapted to changing professional and societal needs and completely in place by the 1994-95 academic year, was influenced by the recommendations of the General Professional Education of the Physician (GPEP) Report, issued by the Association of American Medical Colleges in 1984. This paper details each of the student-centered curricular changes in the context of the GPEP recommendation that it particularly addresses.

New antiepileptic drugs.

No fewer than eight new antiepileptic drugs (AEDs) with diverse mechanisms of action have been introduced into clinical practice in the 1990s. Short monographs on lamotrigine, vigabatrin, gabapentin, oxcarbazepine, felbamate, topiramate and vigabatrin have been prepared for this review. Details are provided of mechanisms of action, clinical pharmacokinetics and adverse drug interactions. Each section concentrates on the efficacy, tolerability and practical use of these drugs. The areas where they have potential for superiority over the established AEDs have been highlighted. Specific indications and dosage schedules have been provided. As many of these AEDs have, as yet, limited licences, an attempt has been made to identify ongoing studies and important omissions. Where possible, the eventual place of the new agent in the pharmacological management of epilepsy has been assessed. A more limited summary has been included of zonisamide which, although licensed in Japan, is still regarded as an investigational drug elsewhere. Short discussions of three of the most promising investigational compounds, namely remacemide, losigamone and levetiracetam, complete the picture.

Nursing futures: a process to promote change in the delivery of care.

In this era of healthcare reform, performing care using resources in an efficient manner is essential. "Nursing Futures," a process used by a 24-bed general rehabilitation unit in a 530-bed facility, helped the unit to identify key components of care, determine opportunities for improvement, and create a new system for the delivery of care that maximized resources and improved customer satisfaction. A Nursing Futures Committee, composed of nursing staff from all levels and from all shifts, used a continuous quality improvement process to focus on the problems in care delivery and developed ways to solve these problems using the time and talents of registered nurses in the most effective way. The committee also identified expectations of staff by various customer groups; analyzed the delivery system and defined its shortcomings; developed the ideal patient care unit within financial and institutional constraints; and executed the plan, considering cost and evaluation of patient and staff satisfaction before and after the system was implemented. The new system provided consistency in patient care assignments by reorganizing the unit into two nursing teams and by creating a new nursing position, the patient care manager.

Does technique or material used affect bladder tissue reactions when injecting teflon or silicone paste?

OBJECTIVES: Submucosal injections of polytetrafluoroethylene (PTFE) and polydimethylsiloxane (PDMS) paste continue to be used for the correction of vesicoureteral reflux and urinary incontinence. Potential distant particle migration and foreign body tissue reactions are thought to be significantly affected by the technique of injection and the paste material used. A study to determine if injection technique, paste material, or pretreatment of the injection site significantly affects local tissue reaction was performed on 44 New Zealand white rabbits. METHODS: Animals were randomly assigned to undergo four distinct injection treatments into the submucosa or bladder muscularis. Prior to injecting 0.1 cc of the PTFE or PDMS paste, some sites were pretreated with 0.1 cc saline to separate tissue planes, epinephrine to cause vasoconstriction, or doxycycline to provide sclerosis. Pretreatment controls were also performed without injecting PTFE or PDMS paste. Animals were killed, and quadrant bladder biopsies were performed at 1 hour (9), 1 day (9), 7 days (10), 1 month (8), and 6 months (8). A single pathologist, blinded to the injection treatments, performed a histologic evaluation to determine bleb location and the degree of inflammation, fibrosis, and epithelial necrosis. RESULTS: Seven of the 12 submucosal PTFE injection treatments were found on biopsy to be primarily within the muscularis, compared to 1 of 9 with PDMS paste. Three of the 24 PTFE injections could not be found at autopsy. Of these, two were injected into the muscularis, and all were discovered at least 1 month following injection. Particles were present in all 22 PDMS injection sites that were retrieved. Pretreatments, especially with doxycycline, resulted in significant epithelial necrosis at 1 and 7 days. At 1 and 6 months there were no differences in inflammation or fibrosis between PTFE and PDMS or any pretreatment combinations with saline or epinephrine. CONCLUSIONS: Correctly injected, silicone (PDMS) paste appears most likely to remain in the submucosal space. Pretreatment injections may cause early epithelial necrosis. PTFE and PDMS elicit similar foreign body reactions over time.

Physicians for the 21st century: implications for medical practice, undergraduate preparation, and medical education.

Changes in medical education and the practice of medicine have resulted from the push for both education and health care reforms. Undergraduates planning application to medical school should broaden their preparation to include communications, computers, economics, and multicultural educational experiences. To prepare graduates for medical practice in the new millennium, the University of Kentucky College of Medicine has implemented a new curriculum focusing on integration of basic and clinical sciences, primary care in ambulatory sites, health promotion and disease prevention, and attention to the ethical, social, psychologic, and financial impact of disease upon the patient, family, and society.

Synaptic organization of serotonin-like immunoreactive amacrine cells in the larval tiger salamander retina.

Immunoelectron microscopy was used to investigate the ultrastructural features and synaptic relationships of serotonin-like immunoreactive amacrine cells in the larval tiger salamander retina. Serotonin-positive somas exhibited an evenly distributed peroxidase reaction product throughout their cytoplasm. Their nuclei were unstained and possessed indented nuclear membranes. Serotonin-immunoreactive processes were generally stained throughout with the exception of their mitochondria, whose morphology was often disrupted by the staining reaction. They were further characterized by an occasional dense-cored vesicle/s in addition to a generally homogeneous population of small, round, clear synaptic vesicles. Serotonin-immunoreactive amacrine cell processes formed conventional synapses that were characterized by symmetrical synaptic membrane densities. A total of 222 synaptic arrangements were observed that involved the immunostained processes of serotonin-amacrine cells. As presynaptic elements, they primarily contacted amacrine cells processes (37.8%). They also provided substantial synaptic input to processes that lacked synaptic vesicles (16.2%) and whose origin was unidentified. Serotonin-processes provided a far fewer number of synaptic contacts onto the processes of bipolar cells (1.4%) and the somas of cells in the amacrine cell layer (0.5%). As postsynaptic elements, they received synaptic inputs from amacrine cells (27.9%) and bipolar cells (16.2%). With the exception of their synapses onto bipolar cells and the somas of cells in the amacrine cell layer, each of the synaptic relationships of serotonin-amacrine cells was observed in each of sublayers 1-5 of the inner plexiform layer.