The role of noninvasive positive pressure ventilation in community-acquired pneumonia.

BACKGROUND: Despite the increasing use of noninvasive positive pressure ventilation (NIV) in the treatment of critically ill patients with respiratory failure, its role in the treatment of severe community-acquired pneumonia (CAP) is controversial. The aim of this study was to assess the use of NIV in patients with CAP requiring ventilation who are admitted an intensive care unit. METHODS: A retrospective cohort study of all consecutive patients admitted to 3 tertiary care, university-affiliated, intensive care units from January 2007 to January 2012 with the principal diagnosis of CAP and requiring positive pressure ventilation was carried out. The primary outcome was acute hospital mortality. Univariable and multivariable analysis were performed to assess the association between mode of ventilation and death as well as factors associated with failure of NIV. RESULTS: A total of 229 patients were admitted, with 20 patients excluded from the analysis because of do-not-resuscitate orders. Fifty-six percent of patients were initially treated with NIV. Of those, 76% failed NIV and required intubation and invasive ventilation. After adjusting for confounders, no difference in mortality was seen between patients who received NIV as first-line therapy in comparison with patients who received invasive ventilation (odds ratio [OR], 1.63; 95% confidence interval [CI], 0.81-3.28; P = .17). Multivariable analysis demonstrated a trend toward increased NIV failure for the patients who had higher Acute Physiology and Chronic Health Evaluation II scores (P = .07) and vasopressor use at 2 hours after initiation of positive pressure ventilation (OR, 7.5; 95% CI, 1.8-31.3, P = .006). In an adjusted analysis, patients who failed NIV had an increased odds of death when compared with patients who were treated with invasive ventilation (OR, 2.2; 95% CI, 1.0-4.8; P = .03). CONCLUSION: Noninvasive pressure ventilation is frequently used in CAP but is associated with high failure rates. Mortality was not improved in the group of patients who received NIV as first-line therapy despite clinical characteristics that might have suggested a more favorable prognosis. Given the high rates of NIV use, high failure rates, and the hypothesis generating nature of the data in this study, further randomized studies are needed to better delineate the role of NIV in CAP.

Localization of ghrelin and its receptor in the reproductive tract of Holstein heifers.

The aim of this experiment was to localize the mRNA and protein of ghrelin and its active receptor, growth hormone secretagogue 1A (GHS-R1A), within the reproductive tract of dairy cattle. Ghrelin is an orexigenic hormone that has been identified as a potent regulator of energy homeostasis. Recent evidence suggests that ghrelin may also serve as a metabolic signal to the reproductive tract. Ghrelin and GHS-R1A have been identified in the reproductive tract of several species, including humans, mice, and rats. However, ghrelin and GHS-R1A expression have not been described within bovine reproductive tissues. Therefore, the ampulla, isthmus, uterine body, corpus luteum, and follicles were harvested from 3 Holstein heifers (15.91±0.07 mo of age) immediately following exsanguination. Duodenum and hypothalamus were collected as positive controls for ghrelin and GHS-R1A, respectively. Tissues were fixed in 10% formalin and embedded in paraffin for microscopy. Additional samples were stored at -80°C for detection of mRNA. Ghrelin and GHS-R1A mRNA and protein were observed in all tissue types within the reproductive tract of dairy heifers; however, expression appeared to be cell specific. Furthermore, ghrelin protein appeared to be localized to the cytoplasm, whereas GHS-R1A protein was found on the plasma membrane. Within the reproductive tissues, ghrelin mRNA and protein were most abundantly expressed in the ampulla of the oviduct. Concentrations of GHS-R1A were lower than those of ghrelin but differed between tissues. This is one of the first studies to provide molecular evidence for the presence of ghrelin and GHS-R1A within the entire reproductive tract. However, implications for fertility remain to be determined.

T-lymphocyte predominance in lesions of canine coccidioidomycosis.

Coccidioidomycosis is a systemic fungal infection endemic to the southwestern United States. Although cell-mediated immunity is considered critical in control of the infection, little is known of the cellular population in naturally occurring lesions. To characterize the lymphocytic infiltration, archived formalin-fixed, paraffin-embedded tissues (subcutis, pericardium/heart, lung, bone, and synovium) from 18 dogs with coccidioidomycosis were studied with immunohistochemistry for CD3 and CD79a. In nearly all lesions, T lymphocytes were more numerous than B lymphocytes and were distributed throughout the lesion with concentration in the periphery of granulomas, whereas B lymphocytes were mostly confined to the periphery of granulomas. The predominance of T lymphocytes in lesions of canine coccidioidomycosis was independent of the tissue evaluated, the number of intralesional organisms, and the nature or severity of the inflammatory response.

Gene expression profiling in the developing rat brain exposed to ketamine.

Ketamine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with accelerated neuronal apoptosis in the developing rodent brain. In this study, postnatal day (PND) 7 rats were treated with 20 mg/kg ketamine or saline in six successive doses (s.c.) at 2-h intervals. Brain frontal cortical areas were collected 6 h after the last dose and RNA isolated and hybridized to Illumina Rat Ref-12 Expression BeadChips containing 22,226 probes. Many of the differentially expressed genes were associated with cell death or differentiation and receptor activity. Ingenuity Pathway Analysis software identified perturbations in NMDA-type glutamate, GABA and dopamine receptor signaling. Quantitative polymerase chain reaction (Q-PCR) confirmed that NMDA receptor subunits were significantly up-regulated. Up-regulation of NMDA receptor mRNA signaling was further confirmed by in situ hybridization. These observations support our working hypothesis that prolonged ketamine exposure produces up-regulation of NMDA receptors and subsequent over-stimulation of the glutamatergic system by endogenous glutamate, triggering enhanced apoptosis in developing neurons.

Is over-use of proton pump inhibitors fuelling the current epidemic of Clostridium difficile-associated diarrhoea?

Many developed countries have seen an increase in cases of Clostridium difficile-associated diarrhoea (CDAD) in recent years. This has occurred despite heightened awareness of the risks of broad-spectrum antibiotics, overall reduction in antibiotic use and increased focus on hospital hygiene. Some of the increase is due to the introduction of new hypervirulent strains, but it predates the description of these. The epidemic coincides with increased use of proton pump inhibitors (PPIs), much of which is inappropriate according to UK and other national guidelines. Gastric acid is a key host defence against other gastrointestinal infections and epidemiological and animal studies have demonstrated a positive association between incident CDAD and PPI use. An association with recurrence of CDAD after initially successful treatment has also been found. Vegetative C. difficile cells are rapidly killed at normal gastric pH, but survive at the pH found in patients taking PPI. It has recently been shown that vegetative organisms survive long enough on moist surfaces for transmission between patients to occur. We conclude that restricting PPI use to patients with an appropriate indication would reduce unnecessary expenditure on these agents, and might be an additional means of controlling the current epidemic of CDAD.

Abnormal neuronal metabolism and storage in mucopolysaccharidosis type VI (Maroteaux-Lamy) disease.

Mucopolysaccharidosis (MPS) type VI, also known as Maroteaux-Lamy disease, is an inherited disorder of glycosaminoglycan catabolism caused by deficient activity of the lysosomal hydrolase, N-acetylgalactosamine 4-sulphatase (4S). A variety of prominent visceral and skeletal defects are characteristic, but primary neurological involvement has generally been considered absent. We report here that the feline model of MPS VI exhibits abnormal lysosomal storage in occasional neurones and glia distributed throughout the cerebral cortex. Abnormal lysosomal inclusions were pleiomorphic with some resembling zebra bodies and dense core inclusions typical of other MPS diseases or the membranous storage bodies characteristic of the gangliosidoses. Pyramidal neurones were shown to contain abnormal amounts of GM2 and GM3 gangliosides by immunocytochemical staining and unesterified cholesterol by histochemical (filipin) staining. Further, Golgi staining of pyramidal neurones revealed that some possessed ectopic axon hillock neurites and meganeurites similar to those described in Tay-Sachs and other neuronal storage diseases with ganglioside storage. Some animals evaluated in this study also received allogeneic bone marrow transplants, but no significant differences in neuronal storage were noted between treated and untreated individuals. These studies demonstrate that deficiency of 4S activity can lead to metabolic abnormalities in the neurones of central nervous system in cats, and that these changes may not be readily amenable to correction by bone marrow transplantation. Given the close pathological and biochemical similarities between feline and human MPS VI, it is conceivable that children with this disease have similar neuronal involvement.

Pediatric sedation for procedures titrated to a desired degree of immobility results in unpredictable depth of sedation.

OBJECTIVE: To test the hypothesis that the need to attain immobility during pediatric sedation for procedures determines the depth of sedation, which cannot always be predicted. DESIGN: A retrospective review of sedation documents of 301 consecutive sedations of pediatric patients undergoing various procedures SETTING: Division of Critical Care sedation service within a children's hospital. MEASUREMENTS AND MAIN RESULTS: The medical records and sedation forms of our most recent 301 consecutive sedations were retrospectively reviewed. Based on the data gathered, the patients were categorized according to their achieved level of immobility, their level of consciousness according to the definitions of the American Academy of Pediatrics, the procedures for which sedation was administered, and the sedatives used. A total of 125 males and 89 females received 301 sedations. Their ages ranged from 22 days to 29 years (mean 7 y + 6 y). We recognized four categories of immobility for procedures. In category 1, some motion was allowed during painless and noninvasive procedures to the extent that it did not risk the patient nor hinder the successful performance of the procedures. In category 2, the patients were kept motionless during painless and noninvasive procedures. In category 3, the patients were kept motionless during painful and invasive procedures with the addition of local anesthetic. In category 4, the patients remained motionless throughout their painful or invasive procedure without the use of local anesthetics. There were 32, 10, 156 and 103 sedations in each category, respectively. Conscious sedation (CS) was observed in six sedations (19%) in category 1 of immobility; it was observed in none (0%) in category 2, in 4 sedations (2.6%) in category 3, and in 1 sedation (1%) in category 4. Deep sedation (DS) was noted in 26 category 1 sedations (81%), in 10 category 2 sedations (100%), in 136 category 3 sedations (87%), and in 63 category 4 sedations (61%). General anesthesia (GA) was only observed in categories 3 and 4 in 16 sedations (10%) and 39 sedations (38%), respectively. Intravenous (IV) ketamine, as a single agent or in combination with other agents, was the most frequently used sedative (88%) followed by IV benzodiazepines (64%), propofol (39%), opiates (15%), and barbiturates (5%). A total of 59 (19%) adverse events were encountered during the 301 sedations. In categories 1 and 2, no adverse event (0%) was encountered. In category 3, 19 adverse events took place (32%), and 40 adverse events (68%) (P< 0.05) occurred in category 4. CONCLUSIONS: Pediatric sedation results in 4 categories of immobility. Complete immobility during painful and invasive procedures is associated with a higher incidence of adverse events. The depth of sedation (ie, CS, DS, or GA) required to achieve each category of immobility is unpredictable and varies from patient to patient. Thus, granting a limited sedation authority (conscious sedation only) to physicians may be of limited practical value.

Delirium in an intensive care unit: a study of risk factors.

OBJECTIVES: (1) To establish risk factors for the development of delirium in an intensive care unit (ICU) and (2) to determine the effect of delirium on morbidity, mortality and length of stay. DESIGN: Prospective study. SETTING: Sixteen-bed medical/surgical ICU in a university hospital. PATIENTS: Two hundred and sixteen consecutive patients admitted to the ICU for more than 24 h during 5 months were included in the study. INTERVENTIONS: Medical history, selected laboratory values, drugs received and factors that may influence patient psychological and emotional well-being were noted. All patients were screened with a delirium scale. A psychiatrist confirmed the diagnosis of delirium. Major complications such as self-extubation and removal of catheters, as well as mortality and length of stay were recorded. RESULTS: Forty patients (19%) developed delirium; of these, one-third were not agitated. In the multivariate analysis hypertension, smoking history, abnormal bilirubin level, epidural use and morphine were statistically significantly associated with delirium. Traditional factors associated with the development of delirium on general ward patients were not significant in our study. Morbidity (self-extubation and removal of catheters), but not mortality, was clearly increased. CONCLUSION: Predictive risk factors for the development of delirium in studies outside the ICU may not be applicable to critically ill patients. Delirium is associated with increased morbidity. Awareness of patients at risk may lead to better recognition and earlier intervention.

Intensive Care Delirium Screening Checklist: evaluation of a new screening tool.

OBJECTIVE: Delirium in the intensive care unit is poorly defined. Clinical evaluation is difficult in the setting of unstable, often intubated patients. A screening tool may improve the detection of delirium. METHOD: We created a screening checklist of eight items based on DSM criteria and features of delirium: altered level of consciousness, inattention, disorientation, hallucination or delusion, psychomotor agitation or retardation, inappropriate mood or speech, sleep/wake cycle disturbance, and symptom fluctuation. During 3 months, all patients admitted to a busy medical/surgical intensive care unit were evaluated, and the scale score was compared to a psychiatric evaluation. RESULTS: In 93 patients studied, 15 developed delirium. Fourteen (93%) of them had a score of 4 points or more. This score was also present in 15 (19%) of patients without delirium, 14 of whom had a known psychiatric illness, dementia, a structural neurological abnormality or encephalopathy. A ROC analysis was used to determine the sensitivity and specificity of the screening tool. The area under the ROC curve is 0.9017. Predicted sensitivity is 99% and specificity is 64%. CONCLUSION: This study suggests that the Intensive Care Delirium Screening Checklist can easily be applied by a clinician or a nurse in a busy critical care setting to screen all patients even when communication is compromised. The tool can be utilized quickly and helps to identify delirious patients. Earlier diagnosis may lead to earlier intervention and better patient care.

Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens.

Understanding structural requirements for a chemical to exhibit estrogen receptor (ER) binding has been important in various fields. This knowledge has been directly and indirectly applied to design drugs for human estrogen replacement therapy, and to identify estrogenic endocrine disruptors. This paper reports structure-activity relationships (SARs) based on a total of 230 chemicals, including both natural and xenoestrogens. Activities were generated using a validated ER competitive binding assay, which covers a 10(6)-fold range. This study is focused on identification of structural commonalities among diverse ER ligands. It provides an overall picture of how xenoestrogens structurally resemble endogenous 17beta-estradiol (E(2)) and the synthetic estrogen diethylstilbestrol (DES). On the basis of SAR analysis, five distinguishing criteria were found to be essential for xenoestrogen activity, using E(2) as a template: (1) H-bonding ability of the phenolic ring mimicking the 3-OH, (2) H-bond donor mimicking the17beta-OH and O-O distance between 3- and 17beta-OH, (3) precise steric hydrophobic centers mimicking steric 7alpha- and 11beta-substituents, (4) hydrophobicity, and (5) a ring structure. The 3-position H-bonding ability of phenols is a significant requirement for ER binding. This contributes as both a H-bond donor and acceptor, although predominantly as a donor. However, the 17beta-OH contributes as a H-bond donor only. The precise space (the size and orientation) of steric hydrophobic bulk groups is as important as a 17beta-OH. Where a direct comparison can be made, strong estrogens tend to be more hydrophobic. A rigid ring structure favors ER binding. The knowledge derived from this study is rationalized into a set of hierarchical rules that will be useful in guidance for identification of potential estrogens.

QSAR models using a large diverse set of estrogens.

Endocrine disruptors (EDs) have a variety of adverse effects in humans and animals. About 58,000 chemicals, most having little safety data, must be tested in a group of tiered assays. As assays will take years, it is important to develop rapid methods to help in priority setting. For application to large data sets, we have developed an integrated system that contains sequential four phases to predict the ability of chemicals to bind to the estrogen receptor (ER), a prevalent mechanism for estrogenic EDs. Here we report the results of evaluating two types of QSAR models for inclusion in phase III to quantitatively predict chemical binding to the ER. Our data set for the relative binding affinities (RBAs) to the ER consists of 130 chemicals covering a wide range of structural diversity and a 6 orders of magnitude spread of RBAs. CoMFA and HQSAR models were constructed and compared for performance. The CoMFA model had a r2 = 0.91 and a q2LOO = 0.66. HQSAR showed reduced performance compared to CoMFA with r2 = 0.76 and q2LOO = 0.59. A number of parameters were examined to improve the CoMFA model. Of these, a phenol indicator increased the q2LOO to 0.71. When up to 50% of the chemicals were left out in the leave-N-out cross-validation, the q2 remained significant. Finally, the models were tested by using two test sets; the q2pred for these were 0.71 and 0.62, a significant result which demonstrates the utility of the CoMFA model for predicting the RBAs of chemicals not included in the training set. If used in conjunction with phases I and II, which reduced the size of the data set dramatically by eliminating most inactive chemicals, the current CoMFA model (phase III) can be used to predict the RBA of chemicals with sufficient accuracy and to provide quantitative information for priority setting.

Corticosteroid-responsive thrombocytopenia in two beef cows.

Corticosteroid-responsive thrombocytopenia was identified in 2 beef cows. Clinical findings in 1 cow included hematoma formation, petechiation of mucous membranes, anemia, and persistent thrombocytopenia. Cow 2 was in its fourth month of gestation and had epistaxis, nasal mucosal petechiation, anemia, and thrombocytopenia. Treatment included parenteral administration of corticosteroids at immunosuppressive dosages. Cow 1 had a history of chronic hematoma formation and responded to long-term treatment with dexamethasone, but it relapsed 2 months after treatment was discontinued. Cow 2 had acute onset of clinical signs, responded to short-term treatment with prednisone, delivered a full-term, healthy calf, and remained clinically normal for at least 1 year after treatment was completed. Reported causes of thrombocytopenia in ruminants were ruled out or seemed unlikely; a definitive cause for thrombocytopenia in the 2 cows could not be established.

Ocular Onchocerca infections in two dogs in western United States.

Two dogs, one from California and one from Arizona, were found to have aberrant infections caused by filarial nematodes of the genus Onchocerca. In both cases, the parasites are localized in or near the eye. In one case the worm was located in the cornea and was surgically removed. In the second case, a very marked granulomatous reaction was induced in the retrobulbar space, mimicking an abscess. This eye was enucleated. The worms in both instances were female, and were gravid, i.e. contained microfilariae in utero, indicating that a male worm(s) had been present and mating had occurred. The exact identity of the species of Onchocerca responsible cannot be determined, although the features observed are most like Onchocerca lienalis of cattle. These cases represent the fourth and fifth such cases reported from the US, and are especially interesting because of the unusual location of the worms, the small number of recognized cases, and the similarity to a recent zoonotic human infection.

Effect of hyperbaric oxygen treatment on incorporation of an autogenous cancellous bone graft in a nonunion diaphyseal ulnar defect in cats.

OBJECTIVE: To determine whether hyperbaric oxygen treatment (HBOT) would affect incorporation of an autogenous cancellous bone graft in diaphyseal ulnar defects in cats. ANIMALS: 12 mature cats. PROCEDURE: Bilateral nonunion diaphyseal ulnar defects were created in each cat. An autogenous cancellous bone graft was implanted in 1 ulnar defect in each cat, with the contralateral ulnar defect serving as a nongrafted specimen. Six cats were treated by use of hyperbaric oxygen at 2 atmospheres absolute for 90 minutes once daily for 14 days, and 6 cats were not treated (control group). Bone labeling was performed, using fluorochrome markers. Cats were euthanatized 5 weeks after implanting, and barium sulfate was infused to evaluate vascularization of grafts. Ulnas were evaluated by use of radiography, microangiography, histologic examination, and histomorphometric examination. RESULTS: Radiographic scores did not differ between treatment groups. Microangiographic appearance of grafted defects was similar between groups, with all having adequate vascularization. Differences were not observed between treated and nontreated groups in the overall histologic appearance of decalcified samples of tissue in grafted defects. Mean distance between fluorescent labels was significantly greater in cats given HBOT than in nontreated cats. Median percentage of bone formation in grafted defects was significantly greater in cats given HBOT. CONCLUSIONS: Hyperbaric oxygen treatment increased the distance between fluorescent labels and percentage of bone formation when incorporating autogenous cancellous bone grafts in induced nonunion diaphyseal ulnar defects in cats, but HBOT did not affect revascularization, radiographic appearance, or qualitative histologic appearance of the grafts.

The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands.

We have utilized a validated (standardized) estrogen receptor (ER) competitive-binding assay to determine the ER affinity for a large, structurally diverse group of chemicals. Uteri from ovariectomized Sprague-Dawley rats were the ER source for the competitive-binding assay. Initially, test chemicals were screened at high concentrations to determine whether a chemical competed with [3H]-estradiol for the ER. Test chemicals that exhibited affinity for the ER in the first tier were subsequently assayed using a wide range of concentrations to characterize the binding curve and to determine each chemical's IC50 and relative binding affinity (RBA) values. Overall, we assayed 188 chemicals, covering a 1 x 10(6)-fold range of RBAs from several different chemical or use categories, including steroidal estrogens, synthetic estrogens, antiestrogens, other miscellaneous steroids, alkylphenols, diphenyl derivatives, organochlorines, pesticides, alkylhydroxybenzoate preservatives (parabens), phthalates, benzophenone compounds, and a number of other miscellaneous chemicals. Of the 188 chemicals tested, 100 bound to the ER while 88 were non-binders. Included in the 100 chemicals that bound to the ER were 4-benzyloxyphenol, 2,4-dihydroxybenzophenone, and 2,2'-methylenebis(4-chlorophenol), compounds that have not been shown previously to bind the ER. It was also evident that certain structural features, such as an overall ring structure, were important for ER binding. The current study provides the most structurally diverse ER RBA data set with the widest range of RBA values published to date.

Automatic control of pressure support mechanical ventilation using fuzzy logic.

There is currently no universally accepted approach to weaning patients from mechanical ventilation, but there is clearly a feeling within the medical community that it may be possible to formulate the weaning process algorithmically in some manner. Fuzzy logic seems suited this task because of the way it so naturally represents the subjective human notions employed in much of medical decision-making. The purpose of the present study was to develop a fuzzy logic algorithm for controlling pressure support ventilation in patients in the intensive care unit, utilizing measurements of heart rate, tidal volume, breathing frequency, and arterial oxygen saturation. In this report we describe the fuzzy logic algorithm, and demonstrate its use retrospectively in 13 patients with severe chronic obstructive pulmonary disease, by comparing the decisions made by the algorithm with what actually transpired. The fuzzy logic recommendations agreed with the status quo to within 2 cm H(2)O an average of 76% of the time, and to within 4 cm H(2)O an average of 88% of the time (although in most of these instances no medical decisions were taken as to whether or not to change the level of ventilatory support). We also compared the predictions of our algorithm with those cases in which changes in pressure support level were actually made by an attending physician, and found that the physicians tended to reduce the support level somewhat more aggressively than the algorithm did. We conclude that our fuzzy algorithm has the potential to control the level of pressure support ventilation from ongoing measurements of a patient's vital signs.

Ceftriaxone-related fatal hemolysis in an adolescent with perinatally acquired human immunodeficiency virus infection.

A 14-year-old girl with perinatally acquired human immunodeficiency virus infection had fatal intravascular hemolysis after intravenous administration of ceftriaxone. Laboratory studies confirmed the presence of an antibody against ceftriaxone in the serum and on the patient's red blood cells. No evidence of sepsis, glucose-6-phosphate dehydrogenase deficiency or anaphylaxis was found.

Urine glycosaminoglycan concentrations in mucopolysaccharidosis VI-affected cats following bone marrow transplantation or leukocyte infusion.

Urinary glycosaminoglycan (GAG) concentrations were determined in nineteen normal cats (eleven kittens and eight adult cats), eighteen mucopolysaccharidosis VI (MPS VI)-affected untreated cats (ten kittens and eight adult cats), thirteen cats MPS VI-affected cats following bone marrow transplants (BMT), and two MPS VI-affected cats following intravenous infusion of leukocytes from normal cats. Mucopolysaccharidosis VI-affected cats treated with BMT had a precipitous decrease in urinary GAG by day 7 post-BMT, then a transient increase just prior to engraftment, followed by a sustained decrease to within, or near, the range of urinary GAG concentration established for normal cats. The pre-engraftment changes in urinary GAG excretion were reproduced by leukocyte infusion. After infusion of comparable members of normal peripheral blood leukocytes, a significant decrease in urinary GAG concentrations, specifically dermatan sulfate (DS), was seen with a nadir at day 5 post-infusion, followed by a return by day 9 to pre-infusion values. Post-engraftment, a continued low urinary GAG concentration with a specific decrease in DS can be utilized to document successful autologous engraftment in MPS VI-affected cats.

In vitro embryotoxicity of carbamazepine and carbamazepine-10, 11-epoxide.

Carbamazepine (Tegretol, CBZ) is an anticonvulsant drug that is very effective in the treatment of tonic-clonic seizures and is gaining acceptance as a treatment for various psychiatric disorders. The drug is embryotoxic in rodents and has been reported to produce neural tube defects in approximated 1% of prenatally exposed human offspring. It is metabolized by the cytochrome P-450 system to a stable, pharmacologically active epoxide intermediate, carbamazepine-10, 11-epoxide. It is currently unknown whether the parent compound, the epoxide intermediate or some other metabolite is the embryotoxic agent. The present study was designed to determine the embryotoxicity of CBZ and its epoxide intermediate (CBZ-E) in a rodent whole embryo culture system. Rat embryos were cultured beginning on day 9 of gestation (GD 9), and mouse embryos were cultured beginning in GD 8. All embryos were cultured for 48 hr in medium containing various concentrations of either CBZ or CBZ-E. Mice were more sensitive to the effects of CBZ than were rats. The parent compound was embryotoxic to mouse embryos at concentrations as low as 12 micrograms, but it was only embryotoxic at 60 micrograms/ml to rat embryos. CBZ-E was not embryotoxic to either species at concentrations as high as 48 micrograms/ml. These results suggest that the parent compound is the embryotoxic agent and that the epoxide intermediate plays no role in the drug's embryotoxic mechanism.

Evaluation of shelf arthroplasty as a treatment for hip dysplasia in dogs.

OBJECTIVE: To evaluate effects of shelf arthroplasty on coxofemoral joint laxity and progression of degenerative joint disease in young dogs with hip dysplasia. DESIGN: Prospective, controlled study. ANIMALS: 10 dogs between 10 and 24 months old and weighing between 20 and 27 kg. All dogs had bilateral coxofemoral joint laxity (i.e., an Ortolani's sign). PROCEDURE: In all dogs, shelf arthroplasty was performed on the right coxofemoral joints, and a sham procedure was performed on the left. Dogs were evaluated before and after surgery by means of lameness assessment, coxofemoral joint palpation and goniometry, thigh circumference measurement, and radiography. RESULTS: There were no significant changes in coxofemoral joint mobility, range of motion, joint laxity, degree of degenerative joint disease, or thigh circumference during the study. A greater amount of periacetabular bone formed on the right side than on the left side; however, dogs did not develop large bony shelves, and the amount of periarticular bone decreased over time. The polymer implants remained in their original position and were encapsulated by fibrous tissue. There was no histologic evidence of osteoconduction by the implants. CLINICAL IMPLICATIONS: The polymer implants used in this procedure do not appear to be osteoconductive. Shelf arthroplasty was associated with minimal morbidity and was not associated with serious adverse sequelae in this study, but the procedure did not alter the progression of hip dysplasia in these dogs. We cannot advocate shelf arthroplasty using this polymer as a treatment for dogs with hip dysplasia.