Cardiopulmonary effects of combined xylazine-guaiphenesin-ketamine infusion and extradural (inter-coccygeal lidocaine) anaesthesia in calves.

OBJECTIVE: To investigate the cardiopulmonary effects of a xylazine-guaiphenesin-ketamine infusion combined with inter-coccygeal extradural (lidocaine) anaesthesia in calves. STUDY DESIGN: Prospective study. ANIMALS: Five Holstein Friesian calves (one steer, four heifers) aged 6 weeks weighing 65.2 +/- 2.7 kg. MATERIALS AND METHODS: Calves were anaesthetized with isoflurane in oxygen for instrumentation. At least 12 hours later, xylazine (0.2 mg kg(-1) i.m.) was given. After 15 minutes, an infusion of xylazine hydrochloride (0.1 mg mL(-1)), guaiphenesin (50 mg mL(-1)) and ketamine (1 mg mL(-1)) (X-G-K) was infused at a rate of 1.1 mL kg(-1) hour-1 i.v. Oxygen (4 L minute(-1)) was delivered by nasotracheal tube 30 minutes later. Inter-coccygeal (Co1-Co2) extradural anaesthesia (lidocaine 2%, 0.18 mL kg(-1)) was administered 30 minutes later. Cardiopulmonary variables were obtained in the unsedated standing calves 10 minutes after xylazine, 15 and 30 minutes after X-G-K without O2, 15 and 30 minutes after X-G-K with O2 and 5, 15, 30, 45 and 60 minutes after extradural anaesthesia. Data were analysed using a repeated measurement analysis of variance including an autoregressive covariance structure of order 1 (correlations at different time intervals). RESULTS: Xylazine caused significant (p<0.05) decreases in heart rate (HR), cardiac output (Qt) and index (CI), stroke volume and stroke index, mean, systolic and diastolic arterial blood pressure (MAP, SAP, DAP), left (LVWSI) and right ventricular stroke work index (RVWSI), mean, systolic and diastolic pulmonary arterial pressure (MPAP, SPAP, DPAP), arterial pH, arterial oxygen tension (PaO2), arterial base excess, arterial HCO3- concentration, arterial saturation, packed cell volume, arterial and venous oxygen content (CaO2, CvO2), O2 consumption and O2 delivery (VO2, DO2). Increases in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were observed. During X-G-K infusion without O2, HR, Qt and CI increased gradually while SVR, PVR and MAP decreased. Left ventricular stroke work index and PaO2 remained constant, while O2 supplementation improved PaO2. Coccygeal extradural anaesthesia had little effect on cardiopulmonary variables. Respiratory rate (f) and PaCO2 significantly increased over the experiment. CONCLUSIONS AND CLINICAL RELEVANCE: Xylazine caused adverse cardiopulmonary effects in calves. Improvement occurred during xylazine-guaiphenesin-ketamine infusion. Cardiac index and arterial blood pressure remained below baseline values while sustained increases in respiration rate and PaCO2 were observed. Inter-coccygeal extradural anaesthesia had only minor effects. Oxygen supplementation proved advantageous during guaiphenesin, ketamine and xylazine infusion in healthy calves in combination with coccygeal extradural anaesthesia induced persistent cardiopulmonary depression.

Intensive diabetes management decreases Na-Li countertransport in young subjects with type 1 diabetes and enlarged kidneys.

In type 1 diabetes, increases in sodium-lithium countertransport (Na-Li CT), kidney volume (KV), and albumin excretion rate (AER) may precede the development of persistent microalbuminuria. Limited data exist on reversibility of these factors early in the evolution of diabetic nephropathy. A crossover design was used to study the separate effects of enalapril and intensive diabetes management (IDM) on Na-Li CT, KV and AER in 17 children and adolescents with type 1 diabetes (5-10 years duration) with large kidneys (>275 ml/1. 73 m(2)) and predominantly normoalbuminuria. Subjects were randomized to receive 3 months of either enalapril (0.25 mg/kg/day) or IDM, a 3-month washout, followed by the alternate treatment for 3 months. During IDM, HbA1c decreased 2.5% (pre 9.5+/-0.3% (mean+/-SE), post 7.0+/-0.1%, p<0.0001), but was unchanged while on enalapril (pre 8.8+/-0.3%, post 8.5+/-0.3%, p=0.1). A significant decrease in Na-Li CT was seen with IDM (pre 0.43+/-0.05, post 0.36+/-0.04 mmol/l RBC/h, p=0.006) but not angiotensin converting enzyme inhibition (ACE-i) (pre 0.39+/-0.04, post 0.38+/-0.04 mmol/RBC/h, p=0.4). Neither ACE-i nor IDM affected KV or AER. It is concerning that kidney enlargement does not appear reversible at this early stage in the pathogenesis of diabetic nephropathy, although our conclusions are limited by the short duration of intervention and small sample size. The reduction in Na-Li CT with IDM suggests this may be a potentially modifiable risk factor for diabetic nephropathy.

Intensive diabetes management in adolescents with type 1 diabetes: the importance of intensive follow-up.

Minimal information exists on the education and follow-up required to successfully initiate intensive diabetes management (IDM) in adolescents with type 1 diabetes. We performed a retrospective analysis of HbA1c 3 and 15 months after initiation of IDM in two cohorts: (1) 17 patients who received individualised education in IDM and intensive early follow-up, and (2) 11 patients who participated in group education for initiation of IDM with standard follow-up. Entry HbA1c was higher in the individualised education patients (9.5 +/- 0.3% [mean +/- SE] versus 8.2 +/- 0.4%, p = 0.02). After 3 months of IDM, HbA1c improved in both cohorts reaching similar levels (individualised: 7.0 +/- 0.1%, p < 0.0001 vs entry; group: 7.3 +/- 0.2%, p = 0.05). During the following year, with routine follow-up for both cohorts, HbA1c levels rose approximately 1% as patients reverted to a multiple daily injection regimen. Irrespective of the educational approach, we believe maintenance of IDM and optimal HbA1c requires long-term intensive follow-up.

Systematic reverse genetics of transfer-DNA-tagged lines of Arabidopsis. Isolation of mutations in the cytochrome p450 gene superfamily.

We have developed an efficient reverse-genetics protocol that uses expedient pooling and hybridization strategies to identify individual transfer-DNA insertion lines from a collection of 6000 independently transformed lines in as few as 36 polymerase chain reactions. We have used this protocol to systematically isolate Arabidopsis lines containing insertional mutations in individual cytochrome P450 genes. In higher plants P450 genes encode enzymes that perform an exceptionally wide range of functions, including the biosynthesis of primary metabolites necessary for normal growth and development, the biosynthesis of secondary products, and the catabolism of xenobiotics. Despite their importance, progress in assigning enzymatic function to individual P450 gene products has been slow. Here we report the isolation of the first 12 such lines, including one (CYP83B1-1) that displays a runt phenotype (small plants with hooked leaves), and three insertions in abundantly expressed genes. The DNAs used in this study are publicly available and can be used to systematically isolate mutants in Arabidopsis.

GHB: a home brew.

Gamma-hydroxybutyric acid is an allegedly benign illicit substance that is gaining increasing recognition and attention among substance abusers and athletes. Alongside foreign-made brands, the compound is also easily available, at low cost because of the facility with which it can be produced in one's kitchen. Named by some "Nature's Quaalude" or sold as a health product, it is often used with a false sense of security as it may cause serious and disabling complications, as illustrated by this clinical vignette.

Comparison of Drosophila cytochrome P450 metabolism of natural and model substrates.

Metabolism of some insecticides and toxic natural plant compounds is known to involve cytochrome P450 enzymes. Correlations between insecticide resistance and deethylation of the model substrate, 7-ethoxycoumarin, have prompted its use in screens for potentially resistant insect populations. The applicability of this model substrate as an indicator of the enzyme activities and inductive responsiveness of cytochrome P450 isoforms involved in the metabolism of carnegine was investigated. This toxic isoquinoline alkaloid is found in the host-plants of some species of cactophilic Drosophila. The results show that the ethoxycoumarin (ECOD) assay does not accurately predict carnegine metabolism either quantitatively or with respect to the overall pattern of activity. Therefore, the ECOD assay may be as isozyme-specific in insects as has already been demonstrated in mammals and its use as an indicator of general P450 activity is questionable.

Giant pseudoaneurysm of the extracranial vertebral artery: case report.

Pseudoaneurysms of the extracranial vertebral artery are extremely rare due to their deep location and the anatomical protection of this artery. They can be caused by cervical traumas (firearm injuries, sports, hyperextension of the neck and iatrogeny). The authors report the case of a patient who developed a giant pseudoaneurysm of the extracranial vertebral artery after surgery for the removal of a tumor of the cerebellopontine angle in which surgical lesion of the artery occurred. Treatment was performed by endovascular approach. Literature is reviewed and comments are made on the physiopathogeny of the lesion and the different forms of treatment.

Cloning of wound-induced cytochrome P450 monooxygenases expressed in pea.

Cytochrome P450 monooxygenases (P450s) mediate a wide range of oxidative reactions involved in the biosynthesis of plant secondary metabolites including phenylpropanoids and phytoalexins. To investigate the regulation of these P450s in the phenylpropanoid biosynthetic pathway of pea (Pisum sativum), partial cDNAs representing four distinct P450s expressed in pea seedlings were cloned using a reverse transcription-polymerase chain reaction strategy. One of the corresponding full-length cDNA clones, designated CYP73A9, encodes pea trans-cinnamic acid 4-hydroxylase, which catalyzes the second core reaction in the phenylpropanoid pathway. As expected from its central role in the production of lignin precursors and defense compounds, northern analysis of poly(A)+ mRNA demonstrates that transcripts encoding CYP73A9 are induced appreciably within 3 h after wounding. A second cDNA clone, designated CYP82, encodes a novel P450, whose transcripts are also induced in response to wounding at approximately the same time as CYP73A9 transcripts. Despite the multitude of environmental stimuli known to induce expression of phenylpropanoid pathway enzymes, genomic DNA Southern analysis indicates that each of these P450s is encoded by a low copy number (possibly a single copy) gene family.

Comparison of larval and adult P-450 activity levels for alkaloid metabolism in desertDrosophila.

The cytochrome P-450 monooxygenase system has been implicated in plant utilization by at least three species ofDrosophila (D. nigrospiracula, D. mettleri, andD. mojavensis) that are endemic to the Sonoran Desert of the southwestern United States and northwestern Mexico. Basal and induced levels of total cytochrome P-450 were determined for third-instar and decapitated 2- to 5-day post eclosion adults of the three desert species. Total P-450 levels, both basal and induced for all species assayed, were significantly higher for adults than for larvae by up to 20-fold. On a per organism basis, the levels of in vitro metabolism of the cactus alkaloid, carnegine, and patterns of response to induction by cactus tissue for adult desertDrosophila approximated those of larvae. Induction by phenobarbital, however, resulted in levels of in vitro carnegine metabolism that were up to 5.6-fold higher in adults than in larvae.

Involvement of cytochrome P450 in host-plant utilization by Sonoran Desert Drosophila.

The four Drosophila species endemic to the Sonoran Desert (Drosophila mettleri, Drosophila mojavensis, Drosophila nigrospiracula, and Drosophila pachea) utilize necrotic cactus tissue or soil soaked by rot exudate as breeding substrates. Each Drosophila species uses a different cactus species as its primary host. D. pachea is limited to senita cactus by a biochemical dependency on unusual sterols available only in that cactus. For the other Drosophila species, no such chemical dependencies exist to explain the relationships with their primary host plants. Each cactus species has a different array of allelochemicals that have detrimental effects on non-resident fly species. We have hypothesized that the desert fly-cactus associations are due, in part, to differences between the fly species in their allelochemical detoxication enzymes, the cytochrome P450 system. To test whether P450s are involved in the detoxication of cactus allelochemicals, several experiments were done. (i) The effect of a specific P450 inhibitor, piperonyl butoxide, on larval survival through eclosion on each cactus substrate was investigated. (ii) In vitro metabolism of cactus alkaloids was determined for each Drosophila species. The effects of specific inducers and inhibitors were included in these experiments. (iii) The basal and induced content of cytochrome P450 in each species was determined. The results support the hypothesis that P450 enzymes are involved in host-plant utilization by these Sonoran Desert Drosophila species.