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A 12-y-old castrated male domestic longhaired cat had progressive paraparesis and neurolocalization of L4-S3. MRI revealed a circumscribed intradural-extraparenchymal mass from L5 to S1 that was T2 and short tau inversion recovery hyperintense and strongly contrast-enhancing. Cytologic interpretation of a blind fine-needle aspirate obtained through the L5-L6 space was a tumor of probable mesenchymal origin. A pair of suspect neoplastic cells was seen on a cytocentrifuged preparation of the atlanto-occipital CSF sample, despite a normal nucleated cell count (0 × 10 6 /L) and total protein (0.11 g/L) with only 3 RBCs × 10 6 /L. Clinical signs progressed despite increasing doses of prednisolone and cytarabine arabinoside. Repeat MRI on day 162 demonstrated tumor progression from L4 to Cd2 vertebral segments with intraparenchymal extension. Surgical tumor debulking was attempted, but an L4-S1 dorsal laminectomy revealed diffusely abnormal neuroparenchyma. Intraoperative cryosection favored lymphoma, and the cat was euthanized intraoperatively 163 d following presentation. Postmortem examination was performed, and the final diagnosis was a high-grade oligodendroglioma. This case illustrates the cytologic, cryosection, and MRI features of a unique clinical presentation of oligodendroglioma.

Acute intervertebral disk extrusion (IVDE) is one of the most commonly reported neurologic disorders seen in veterinary practice. There is a recognized subset of IVDE cases that have a hemorrhagic inflammatory reaction within the epidural space that causes compression in addition to compression from herniated disk material. Previous reports have been conflicting in the outcomes of these cases. The goals of this retrospective case-control cross-sectional study are to (1) compare the success rate of routine surgical decompression in dogs with DEEH compression compared to Modified Frankel Score (MFS) matched dogs with non-hemorrhagic disk extrusions; (2) evaluate the extent of spinal cord compression on MRI compared to final patient outcomes in DEEH compression and (3) determine the surgical compression to decompression ratio and its relation to patient outcomes in cases of DEEH compression. A total of 143 dogs were included in this study and divided into two groups: DEEH compression dogs ( n = 78) and non-hemorrhagic IVDE dogs ( n = 65). Outcomes were assigned for each patient [0 = deceased, 1 = alive and non-ambulatory (MFS 0-3), 2 = alive and ambulatory (MFS 4 or 5)] in both groups. Outcomes of DEEH and non-hemorrhagic IVDE did not differ when taken to surgery with comparable success rates when stratified by MFS. Similarly, outcomes did not differ between DEEH and non-hemorrhagic IVDE dogs when assessed by compression to decompression ratio. Dogs with DEEH compression had more compressed sites than dogs with non-hemorrhagic IVDE ( P = 0.001) and had more sites decompressed surgically than dogs with non-hemorrhagic IVDE ( P < 0.001). Consequently, the compression to decompression ratio did not differ between the two groups ( P = 0.52). Our results support the finding that when a similar level of surgical decompression is achieved, dogs with DEEH compression have similar outcomes to dogs with non-hemorrhagic IVDE for similar degrees of neurological dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lawler, Wood, Alleva, Rishniw, Porter and Johnson.)

Background: Hydromyelia is a common magnetic resonance imaging (MRI) finding associated with compressive myelopathy caused by intervertebral disc extrusion (IVDE)., Objectives: To describe the MRI features of hydromyelia and explore its relationship to clinical history, neurological severity, and the duration of cord compression., Animals: Ninety-one client-owned dogs with a focal compressive myelopathy secondary to thoracolumbar IVDE., Methods: A retrospective observational study was conducted in which MRIs were blindly evaluated to grade and localize hydromyelia and measure the degree of spinal cord compression. Duration and severity of clinical signs were recorded. Differences between hydromyelia grades in these variables were statistically assessed using a Wilcoxon and Kruskal Wallis test. Receiver operator curve analysis was used to determine the sensitivity and specificity for duration of clinical signs to predict the presence of hydromyelia., Results: Hydromyelia was identified at sites of IVDE in 84 of 91 dogs. An absence of hydromyelia was associated a with statistically longer duration of clinical signs (mean 73.1, IQR 76 days) when compared to cases with mild (mean 17.7, IQR 7.25 days, P = .006) or severe (mean 17.9, IQR 10.25 days, P = .006) hydromyelia. Duration of clinical signs <14 days was 78.6% sensitive and 85.7% specific for predicting the presence of hydromyelia., Conclusions and Clinical Importance: The MRI finding of hydromyelia might be a predictor of lesion chronicity in focal IVDE, helping to guide planning of hemilaminectomy surgery., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Intracranial neoplasia is relatively common in dogs and stereotactic radiotherapy, surgical debulking, or both, are the most successful treatment approaches. A key component of treatment planning involves delineating tumor margin on magnetic resonance imaging (MRI) examinations. How MRI signal intensity alterations relate to histological tumor margins is unknown., Objectives: Directly compare histological brain sections to MRI sequence images and determine which sequence alteration best correlates with tumor margins., Animals: Five dogs with glioma, 4 dogs with histiocytic sarcoma, and 3 dogs with meningioma., Methods: Retrospective cohort study. Histological brain sections were registered to in vivo MRI scan images obtained within 7 days of necropsy. Margins of signal intensity alterations (T2-weighted, fluid-attenuating inversion recovery [FLAIR], T1-weighted and contrast enhancement) were compared directly to solid tumor and surgical margins identified on histology. Jacquard similarity metrics (JSM) and cross-sectional areas were calculated., Results: In glioma cases, margins drawn around T2-weighted hyperintensity were most similar to surgical margins (JSM, 0.66 ± 0.17) when compared to other sequences. In both meningioma (JSM, 0.57 ± 0.21) and histiocytic sarcoma (JSM, 0.75 ± 0.11) margins of contrast enhancement were most similar to surgical margins., Conclusions and Clinical Importance: Signal intensities correspond to tumor margins for different tumor types and facilitate surgical and radiation therapy planning using MRI images., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 Å and the prodomain-bound BMP9:ALK1 complex at 3.3 Å. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway.

Bone morphogenetic protein 9 (BMP9), a member of the transforming growth factor β (TGFβ) superfamily, is a circulating vascular quiescence and endothelial protective factor, accounting for the majority of BMP activities in plasma. BMP9 and BMP10 bind preferentially to the high-affinity type I receptor activin receptor-like kinase 1 on vascular endothelial cells. Recently, many reports have highlighted the important roles of BMP9 in cardiovascular disease, particularly pulmonary arterial hypertension. In vivo , BMP9 activity and specificity are determined by tightly regulated protein-protein recognition with cognate receptors and a co-receptor, and may also be influenced by other proteins present on the endothelial cell surface (such as low-affinity receptors) and in circulation (such as TGFβ family ligands competing for the same receptors). In this review, we summarise recent findings on the role and therapeutic potential of BMP9 in cardiovascular disease and review the current understanding of how the extracellular protein-protein interaction milieu could play a role in regulating endothelial BMP9 signalling specificity and activity., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

We designed an educational programme for multiple disciplines to improve healthcare students' preparedness to work with people with dementia. It consisted of class-based sessions followed by a volunteer experience interacting with persons with dementia in care homes. This paper discusses the value and impact of this innovative experience.

Background: Dementia is an international health priority and healthcare students need to be prepared to work with people living with dementia. There is a paucity of the literature describing appropriate educational interventions for pre-qualifying healthcare students and even fewer that are evaluated., Methods: Based on available evidence, an education program was developed aiming to increase students' knowledge and confidence in working with people with dementia (PWD). An introductory program (IP) of classroom sessions and workshops was followed by a volunteer care home experience (CHE) (4 × 3 h). Piloted with physiotherapy (IP n = 55; CHE n = 6) and nursing students (IP n = 20; CHE n = 7), using a survey design, knowledge, and perceived confidence for working with PWD were measured at four time points; baseline, after the IP, after the CHE, and six months later. The data were analyzed using paired t-tests or non-parametric equivalents., Results: Knowledge scores increased after the IP (Time 1-2, p < 0.001, n = 48) and increases were retained after six months (Time 1-4, p < 0.001, n = 40). Perceived confidence increased at six months follow up (Time 1-4, p < 0.001, n = 40) with peaks after the IP (Time 1-2, p < 0.001, n = 47) and CHE (Time 2-3, p = 0.004, n = 13). Physiotherapy and nursing students did not differ on knowledge, but nursing students were more confident at baseline and after the IP. Prior experience equated with greater confidence but no more knowledge., Conclusions: Findings indicate that students' knowledge and confidence to work with PWD improves after this educational intervention, with confidence improving more when supplemented by experience.

Objectives: In an aging society, the number of people living with dementia is rapidly increasing. Health care students receive little input on dementia during their pre-registration education, hence there is a requirement to improve education to work with this client group. The review aimed to focus on education on working with people with dementia for pre-registration healthcare students., Design: A comprehensive review of the literature., Data Sources: Online databases Medline, PsychInfo, CINAHL, Science Direct and PubMed were used., Review Methods: The studies were selected according to the following criteria: main focus on education and training on working with people with dementia in pre-registration healthcare programs. Reports that described a training program but did not include evaluation were excluded. For inclusion, studies had to be published in English between January 2007 and March 2014. Identified papers were screened and reviewed by the three authors., Results: Nine studies met the inclusion criteria. Most studies were based in North America, predominantly in nursing and medical education. Educational interventions chiefly aimed to improve students' knowledge, comfort level and attitudes toward people with dementia. It was shown that theoretical input alone did not give students the necessary skills to work with people with dementia. Educational interventions were most effective when a practice based experience was preceded by theoretical preparation., Conclusion: Most of the findings were positive, demonstrating the potential to improve students' knowledge, attitude and comfort level, however methods and evaluation were not always sufficiently reported, making them difficult to use or replicate. This review highlights the need for studies with rigorous methods to determine evidence based best practice for all those working with people with dementia in order to provide effective care and improve their quality of life., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The aim is to describe advanced strategies that can be used to diagnose and treat complications after knee arthrodesis and to describe temporary knee arthrodesis to treat infected knee arthroplasty. Potential difficult complications include nonunited knee arthrodesis, limb length discrepancy after knee arthrodesis, and united but infected knee arthrodesis. If a nonunited knee arthrodesis shows evidence of implant loosening or failure, then bone grafting the nonunion site as well as exchange intramedullary nailing and/or supplemental plate fixation are recommended. If symptomatic limb length discrepancy cannot be satisfactorily treated with a shoe lift, then the patient should undergo tibial lengthening over nail with a monolateral fixator or exchange nailing with a femoral internal lengthening device. If a united knee arthrodesis is infected, the nail must be removed. Then the surgeon has the option of replacing it with a long, antibiotic cement-coated nail. The authors also describe temporary knee arthrodesis for infected knee arthroplasty in patients who have the potential to undergo insertion of a new implant. The procedure has two goals: eradication of infection and stabilization of the knee. A temporary knee fusion can be accomplished by inserting both an antibiotic cement-coated knee fusion nail and a static antibiotic cement-coated spacer. These advanced techniques can be helpful when treating difficult complications after knee arthrodesis and treating cases of infected knee arthroplasty.

We prospectively followed 112 hips, undergoing THA with a Spectron EF stem. At mean follow-up of 11.2years, 21 patients had died. We obtained radiological follow-up in 99% and clinical follow-up in 100% of the surviving 91 hips. Fifty-four percent demonstrated osteolysis in at least one Gruen zone. Twenty-two hips required revision for all causes, with a further five stems radiologically loose. With endpoint being stem revision for aseptic loosening or radiological failure, survivorship at 11years was 0.783. We believe the addition of a rougher surface finish has contributed to the high levels of osteolysis and stem failure seen with the Spectron EF., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of the current study was to determine the incidence of pediatric surgical site infections(SSIs) at an academic children’s hospital in rural sub-Saharan Africa and to identify potentially modifiable risk factors., Methods: Prospectively collected data from 1,008 surgical admissions to Bethany Kids Kijabe Hospital (Kijabe, Kenya) were analyzed retrospectively. Follow-up data were available in 940 subjects., Results: SSIs occurred in 6.8% of included subjects(N = 64). Superficial (69%) and deep (29%) infections of the back (38%) and head (25%) were most common. When comparing children who developed SSI to those who did not, we found that wound contamination classification and duration of operation were the only variables with significant differences between groups., Conclusions: Our rate of SSI among pediatric patients insub-Saharan Africa is the lowest reported in the literature to date. More work is needed to identify modifiable risk factors for pediatric SSI in low- and middle-income countries.

Background: Pediatricians and family physicians are responsible for providing newborn resuscitation, yet Accreditation Council for Graduate Medical Education requirements for training in this area during residency differ markedly for the two specialties. Our objectives were to determine (1) the extent to which neonatal resuscitation training differs for pediatric and family medicine residents; (2) the extent to which general pediatricians and family physicians engage in newborn resuscitation in their practice; and (3) whether use of resuscitation skills differs between urban/suburban and rural providers., Methods: We surveyed a national cohort of pediatricians and family physicians who obtained board certification between 2001 and 2005. Data were analyzed based on type of physician and setting of current practice., Results: Survey response rate was 22% (382 of 1736). Compared with family medicine physicians, pediatricians received more neonatal resuscitation training during residency. Most members of both groups had attended no deliveries in the year prior to the survey (75% [111 of 148] versus 74% [114 of 154]). In their current practice, the groups were equally likely to have provided a newborn bag and mask ventilation, chest compressions, and resuscitation medications. Pediatricians were more likely than family physicians to have attempted to either intubate a newborn (20% [28 of 148] versus 10% [16 of 153]; P  =  .0495) or insert umbilical catheters (15% [22 of 148] versus 5% [8 of 153]; P  =  .005). Regardless of specialty, rural physicians were much more likely to report that they attended deliveries (61% [41 of 67] versus 15% [36 of 234]; P < .001). Among rural pediatricians attending deliveries, 44% (7 of 16) reported feeling inadequately prepared for at least one delivery in the past year., Conclusions: Few primary care pediatricians and family physicians provide newborn resuscitation after residency. For those who do attend deliveries, current training 5 provide insufficient preparation. Flexible, individualized residency curricula could target intensive resuscitation training to individuals who plan to practice in rural areas and/or attend deliveries after graduation.

Purpose: We undertook the current study to update the literature on pediatric splenectomy in the age of minimally invasive proficiency among pediatric surgeons. The study is designed to address specific concerns among surgeons about the suitability of the laparoscopic approach in specific situations and among hematologists about the relative benefits and risks of splenectomy in children., Methods: Retrospective analysis of clinicopathologic data for 118 children who underwent open (OS) or laparoscopic (LS) splenectomy at an urban tertiary children's hospital from January 2000 to July 2008., Results: One hundred and three cases (87%) were started as LS. Operative times were equivalent for LS and OS (P = 0.8). In the LS group, there were four conversions (3.9%) from LS to OS and five early post-operative complications (4.9%). Median length of stay was 2 days for LS and 4 days for both OS and LS converted to OS (P < 0.0001). The ten largest spleens removed by LS had greater mass (P = 0.02) and tended to have greater volume (P = 0.1) than those removed by OS. Children with hereditary spherocytosis, ITP, and hemoglobinopathy had favorable clinical outcomes, regardless of operative approach. There were no cases of overwhelming post-splenectomy sepsis in this series., Conclusions: Laparoscopic splenectomy is the preferred approach for splenectomy in children with hematological diseases, with or without splenomegaly. Compared to open splenectomy, laparoscopic splenectomy has equivalent operative time and improved length of stay. Both approaches have excellent therapeutic outcomes for appropriate indications.

Introduction: We have developed a collaborative approach to pediatric thyroid surgery, with operations performed at a children's hospital by a pediatric surgeon and an endocrine surgeon. We hypothesize that this strategy minimizes specialist-specific limitations and optimizes care of children with surgical thyroid disease., Methods: Data from all partial and total thyroidectomies performed by the pediatric-endocrine surgery team at a tertiary children's hospital between 1995 and 2009 were collected and analyzed retrospectively. Statistical analyses were performed with IBM SPSS software (SPSS, Chicago, IL)., Results: Thirty-five children met the inclusion criteria (69% female; median age, 13 years; median follow-up, 1119 days). The indications for operation were thyroid nodule (71%), genetic abnormality with predisposition to thyroid malignancy (17%), multinodular goiter (5.7%), Grave disease (2.9%), and Hashimoto thyroiditis (2.9%). Sixteen children (46%) underwent thyroid lobectomy, and 19 children (54%) underwent total thyroidectomy. Median length of stay was 1 day (1 day after lobectomy vs 2 days after total thyroidectomy, P < .0001). There were 4 cases of transient hypocalcemia after total thyroidectomy, but there were no nerve injuries or other in-hospital complications in either group (overall complication rate, 11%)., Conclusions: For pediatric thyroidectomy and thyroid lobectomy, collaboration of high-volume endocrine and pediatric surgeons as well as pediatric endocrinologists at a dedicated pediatric medical center provides optimal surgical outcomes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to evaluate the outcome of nonoperative vs operative management of blunt pancreatic trauma in children., Methods: Retrospective review of pancreatic injuries from 1995 to 2006 at an urban level I regional pediatric trauma center., Results: Forty-three children with pancreatic injury were included in the analysis. Injuries included grade I (n = 18), grade II (n = 6), grade III (n = 17), and grade IV (n = 2). For grade II to IV injuries, patients managed operatively (n = 14) and nonoperatively (n = 11) had similar lengths of stay and rates of readmission, despite increased pancreatic complications (PCs) in the nonoperative cohort (21% vs 73%; P = .02). There was a trend toward increased non-PCs in patients managed with resection (P = .07). Twelve patients underwent successful diagnostic endoscopic retrograde cholangiopancreatography in which duct injury was identified. In this group, nonoperative management was pursued in 6 patients but was associated with increased rates of PC (86% nonoperative vs 29% operative; P = .02)., Conclusions: Operative management of children with grades II to IV pancreatic injury results in significantly decreased rates of PCs but fails to decrease length of stay in the hospital, possibly as a result of non-PCs. Endoscopic retrograde cholangiopancreatography may serve as a useful diagnostic modality for guiding operative vs nonoperative management decisions., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: Predicting the response to splenectomy in children with immune thrombocytopenic purpura (ITP) continues to be a clinical challenge. The purpose of this study is to identify preoperative predictors of outcome for splenectomy in children with ITP., Methods: The charts of 19 children who underwent splenectomy for ITP were retrospectively reviewed. Platelet responses to treatment are categorized as complete response (CR, > or =150,000/microL), partial response (PR, > or =50,000 but <150,000/microL), or nonresponse (NR, <50,000/microL)., Results: After splenectomy, 13 patients (68%) had CR, 3 (16%) had PR, and 3 (16%) had NR. No correlation existed between CR to splenectomy and any of the following: age, platelet count at diagnosis, last platelet count before splenectomy, platelet count on postoperative day 1, or responses to preoperative intravenous immunoglobulin, WinRho, or Rituximab. However, all 7 patients who had NR to a full course of steroids subsequently had CR to splenectomy. Nonresponse to steroid therapy was directly correlated with CR to splenectomy (P = .01, Fisher's Exact test). Furthermore, postsplenectomy platelet counts were inversely related to peak platelet response to steroids (correlation coefficient = -0.68, P = .01)., Conclusions: Preoperative responsiveness to steroid therapy, as measured by peak platelet count, predicts NR to splenectomy for ITP in children, whereas NR to steroid therapy is highly correlated with CR to splenectomy. These findings challenge the widely held notion that steroid responsiveness portends a favorable outcome after splenectomy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Thymoglobulin (Genzyme, Cambridge, MA) is an antithymocyte globulin preparation used for induction immunosuppression therapy in solid organ transplantation. It is being utilized with increasing frequency in orthotopic liver transplantation (OLT) in an effort to minimize or delay the use of calcineurin inhibitors due to their inherent nephrotoxicity. Experience with thymoglobulin in OLT remains limited. We report a case of serum sickness in a patient who received thymoglobulin following OLT. The patient experienced intermittent fevers, polyarthralgia, and acute renal failure 9 days after completion of thymoglobulin administration. The patient's symptoms resolved rapidly and completely with a course of intravenous steroids. We review a set of diagnostic criteria for serum sickness and emphasize the importance of early recognition of the process. Early treatment of serum sickness with steroids or plasmapheresis is highly effective and can reduce unnecessary morbidity from this unusual sequela of induction immunosuppression with antithymocyte globulin.

Beware of the unpublished abstract! What is the publication rate of abstracts presented at Musculoskeletal Tumor Society meetings, and how does this compare with other orthopaedic and medical meetings? Three hundred thirty-six podium presentations from six annual meetings were identified and their publication was searched at a minimum of 3 years after the event. An effort was made to determine what percent of these abstracts eventually were published in a peer-reviewed journal. It was determined that 137 abstracts were published for a publication rate of 41%. The average time between presentation at the meeting and publication was 21.8 plus or minus 13.5 months. The published articles appeared in 48 peer-reviewed journals. The rate of publication and time until publication was similar to other orthopaedic meetings and to other medical disciplines. Changes to the cohort, title, or authors occurred in approximately (1/3) of the published articles compared with the abstracts. These results suggest that for various reasons the majority of presented material at Musculoskeletal Tumor Society meetings may not survive peer review and may not be scientifically valid.

Background: Dezinamide (DZM, ADD 94057) is a potential antiepileptic drug that binds to the voltage-sensitive sodium channel and showed preliminary evidence of efficacy and safety in an open-label study., Methods: Our double-blind, placebo-controlled trial at two sites used an n-of-1 (single-patient) design. All 15 patients had medically intractable partial-onset seizures and were comedicated with phenytoin (PHT) only. Treatment was for six 5-week periods (three active paired with three placebo in random sequence). Assuming nonlinear kinetics, we used an initial pharmacokinetic profile to estimate dosages for reaching target plasma concentrations of DZM., Results: Statistically significant seizure reduction was found by both a randomization test (p = 0.0025) and a signed rank test (p = 0.048). Median seizure frequency decreased 37.9%, and 40% of patients had > 50% seizure reduction, both compared with placebo. Pharmacokinetic predictions were not accurate; mean plasma concentrations fell well below target values. Plasma PHT concentrations increased (mean = 17.1%) during DZM treatment. The most common adverse experiences were fatigue, light-headedness, and abnormal gait; five patients required DZM dosage reductions., Conclusions: DZM showed minimal clinical toxicity and significant efficacy despite lower plasma concentrations than predicted by pharmacokinetics. This trial establishes the suitability of the n-of-1 design to investigational antiepileptic drug trials.

The effect of haemodilution without volume expansion (isovolemic haemodilution) was assessed with respect to blood flow and oxygen transport across stenotic lesions of progressive severity in the dog carotid artery. As the mean haematocrit (Hct) was reduced from 40 +/- 1% (+/- SEM) to 32 +/- 0% (p less than 0.001), reductions in vascular resistance were significant across the 90% (p less than 0.001) and 95% (p less than 0.0003) relative carotid stenoses. Isovolemic haemodilution reduced fresh blood viscosity significantly by 27 +/- 3% (p less than 0.001) and 42 +/- 4% (p less than 0.001) at the low shear rates of 10 sec-1 and 1 sec-1 which are typical of low-flow states. Following a 20% reduction in Hct 30 to 35% increase (p less 0.001) in carotid blood flow occurred at non-critical degrees of stenosis while a mean 83% increase (p less than 0.001) occurred at the highly critical 95% relative stenosis. Oxygen transport after a 22% decrease in blood haemoglobin was significantly increased by 28% (p less than 0.01) at the 95% relative stenosis level. These data provide a physiologic rationale for the beneficial effects of haemodilution in acute cerebral ischaemia, cerebral vasospasm and cerebral revascularization or carotid endarterectomy.

The "product enantioselectivity" associated with the urinary excretion of the phenobarbital N-glucoside conjugates has not been determined previously. A liquid chromatography method using gradient elution was developed for quantifying both phenobarbital N-glucoside conjugates, phenobarbital, and p-hydroxyphenobarbital. Following a single oral dose of phenobarbital to male Caucasian and Oriental subjects, both phenobarbital N-glucoside conjugates were observed in the urine. In seven subjects, 3.3-10.6% of the phenobarbital dose was detected as a single phenobarbital N-glucoside (S configuration at the C-5 position of the barbiturate ring). The other phenobarbital N-glucoside diastereomer accounted for less than 1.5% of the phenobarbital dose. The urinary excretion of the major phenobarbital N-glucoside diastereomer paralleled the urinary excretion of phenobarbital and was comparable in both Caucasian and Oriental subjects. These results indicate a pronounced selectivity for the formation and/or urinary excretion of the phenobarbital N-glucosides.

A high-performance liquid chromatography (HPLC) procedure has been developed for the determination of azapropazone and its 6-hydroxy metabolite in plasma and urine. The procedure is simple and rapid since extraction of the drug and its metabolite is not required. Plasma proteins are precipitated with methanol, and the supernate is injected onto a reverse-phase HPLC column. With photometric detection at 254 nm, the procedure can determine as little as 0.4 micrograms/ml azapropazone in plasma or urine and 1.5-3 micrograms/ml of the metabolite in urine, depending upon the level of interference. The procedure has been used successfully in single-dose pharmacokinetic and bioavailability studies of azapropazone dosage forms.

The availability of various dosages of insulin from a new collapsible polyolefin bottle fitted with a conventional polyvinyl chloride administration set was studied. Intravenous solutions containing various dosages of insulin (20, 40, 70, and 100 units), to which 125I-labeled insulin was added, were prepared. Solutions were mixed and delivered at a maintained flow rate of 125 ml/hour. Effluents were collected at 15, 30, 45, and 60 minutes and then at hourly intervals up to seven hours. One-milliliter samples were drawn from the end of the administration set at the end of each interval, and the level of radioactivity in the sample was measured. Greater percentages of binding occurred at the lower levels of insulin added. Saturation limits of 7.8, 2.7, and 5.4 units were found for the system, administration set, and bottle, respectively. Adsorption values for this bottle were less than that found in another study for polyvinyl chloride.

Saliva drug concentrations are a function of the saliva flow rate at which they are collected. Increased saliva flow rate tends to restore the salivary concentration towards the free unbound plasma concentration of drug. For those drugs excluded from the saliva relative to their free plasma concentration, stimulation increases the observed drug levels in the saliva. For those drugs concentrated in the saliva relative to their free plasma concentration, stimulation decreases the observed drug levels in the saliva.

Central nervous system gamma-aminobutyric acid (GABA) activity was demonstrated to be an age- and sex-dependent phenomenon through the study of GABA concentration in lumbar CSF obtained from 87 drug-free normal individuals. Evaluation of the data from homogeneous subgroups of this population disclosed that both the propensity of lumbar CSF GABA levels to decrease with age and the magnitude of the rostrocaudal GABA concentration gradient are more pronounced in females, suggesting possible neuroendocrine involvement. Thus, age and sex are important variables that normally influence central GABAergic activity. Patient populations included in clinical investigations must be age- and sex-matched to avoid invalid conclusions biased by these physiologic variations in CSF GABA concentrations.