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Biomedical subjects

J Caldwell

Publications and source records attributed to J Caldwell.

At least 55 records · Page 3Linked to original sources
PubMed1997

Effect of dexmedetomidine on lumbar cerebrospinal fluid pressure in humans.

UNLABELLED: Dexmedetomidine's potential for analgesia without respiratory depression and its opioid- and anesthetic-sparing properties make it an attractive choice as an anesthetic adjunct for patients undergoing neurosurgery. However, the effects of dexmedetomidine on intracranial pressure are not known. We therefore studied the effect of dexmedetomidine on lumbar cerebrospinal fluid (CSF) pressure in patients after transphenoidal pituitary tumor surgery. Sixteen transphenoidal pituitary tumor surgery patients were randomized to receive placebo (n = 9) or dexmedetomidine (n = 7) for 60 min in the postanesthesia care unit. The study drug was administered by a continuous computer-controlled infusion to achieve an estimated plasma dexmedetomidine concentration of 600 pg/mL, the highest plasma concentration that has been used for clinical purposes. Patient-controlled analgesia was used to administer morphine for postoperative discomfort. Lumbar CSF pressure (via lumbar intrathecal catheter), intraarterial blood pressure, and heart rate were monitored continuously. There was no change in lumbar CSF pressure in either group. The highest values obtained were 19 mm Hg in the dexmedetomidine group and 20 mm Hg in the placebo group. During infusion, mean arterial pressure decreased from 103 +/- 10 mm Hg to 86 +/- 6 mm Hg (P < 0.05), heart rate decreased from 77 +/- 12 bpm to 64 +/- 7 bpm (P < 0.05), and cerebral perfusion pressure decreased from 95 +/- 8 mm Hg to 78 +/- 6 mm Hg (P < 0.05) in the dexmedetomidine group, but not in the placebo group. We conclude that dexmedetomidine does not have an effect on lumbar CSF pressure in patients with normal intracranial pressure who have undergone transphenoidal pituitary hypophysectomy. IMPLICATIONS: The effects of dexmedetomidine (an alpha2-agonist) or placebo on lumbar cerebrospinal fluid pressure, measured via an intrathecal catheter, were studied postoperatively in 16 patients. Dexmedetomidine had no effect on lumbar cerebrospinal fluid pressure. We will continue to investigate the potential utility of dexmedetomidine for neurosurgical anesthesia.

Adjuvants, Anesthesia↗
PubMed1996

Crystallization and preliminary X-ray analysis of brazzein, a new sweet protein.

Brazzein is a sweet protein isolated from a wild African plant Pentadiplandra brazzeana. Brazzein is the smallest (molecular mass = 6473 Da) and the most water-soluble protein sweetener discovered so far and is highly thermostable. Crystals were grown by vapor diffusion using sodium sulfate as a precipitant. They belong to the tetragonal space group I4(1)22 with unit-cell parameters a = b = 61.4, c = 59.6 A and with one molecule in the asymmetric unit. The crystals diffract to 1.8 A resolution using synchrotron radiation.

Journal Article↗
PubMed1996

Importance of stereospecific bioanalytical monitoring in drug development.

The role of the bioanalyst in the support of drug discovery and development is described with particular emphasis upon stereospecific assays for the individual optical isomers of chiral drugs. The significance of the stereochemical aspects of pharmacokinetics and drug metabolism in both preclinical and clinical development is summarized and illustrated with reference to the pharmacogenetic polymorphisms of drug oxidation existing in the human population. The significance of stereochemical considerations in drug metabolism and pharmacokinetics has recently become an issue for both the pharmaceutical industry and the regulatory authorities, driven to a great extent by recent developments in methodology for both the analytical and preparative resolution of racemic drug mixtures. Ths has led to the so-called 'racemate-versus-enantiomer' debate in recent years. The development of regulatory attitudes in the major jurisdictions of the world to the development of new drugs containing one or more chiral centres is outlined.

Drug Design↗
PubMed1996

Factors affecting the metabolism of cinnamyl anthranilate in the rat and mouse.

The biological actions of cinnamyl anthranilate are dependent on both dose size and animal species. The present study aimed to examine metabolism as a possible source of explanation for these differences. [3-14C]Cinnamyl anthranilate was synthesized, injected ip into male Fischer 344 (F344) rats and CD-1 mice and urine and faeces collected for 3 days. The pattern of elimination of 14C was the same in both species, with the bulk of the administered material recovered in urine over the first 24 hr. Urinary metabolic profiles were compared by radioHPLC, which showed that the major radioactive excretion product in the rat was hippuric acid accompanied by smaller amounts of benzoic acid. In contrast, mouse urine contained relatively less hippuric acid, more benzoic acid and small amounts (approx. 3% of dose) of unchanged cinnamyl anthranilate. The effect of dose size on urinary metabolites produced by mice was examined using both 3-14C-labelled and unlabelled cinnamyl anthranilate, detected by fluorescence HPLC. Over a dose range of 5 to 250 mg/kg body weight administered ip it was found that at 5 mg/kg body weight no intact ester was excreted in urine whereas at 20 mg/kg body weight or above, the proportion present as the intact ester remained constant. Dietary administration to male and female B6C3F1 mice for 21 days over a dose range of 0 to 30,000 ppm revealed the same qualitative picture with no intact cinnamyl anthranilate detected in urine at or below 1000 ppm (equivalent to 100 mg/kg body weight). A study in human volunteers using a single oral dose of 250 mg failed to reveal any intact cinnamyl anthranilate in 0-24-hr urine. These data support the hypothesis that the peroxisome proliferating action of cinnamyl anthranilate, which is mediated by the intact ester, is manifest only at high doses in species in which its metabolism by hydrolysis is saturated, as a consequence of which the intact ester 'overflows' into urine.

Adult↗
PubMed1996

Lack of influence of modulators of epoxide metabolism on the genotoxicity of trans-anethole in freshly isolated rat hepatocytes assessed with the unscheduled DNA synthesis assay.

The aniseed food flavour trans-anethole was implicated as a weak hepatocarcinogen only in female Sprague Dawley-CD rats administered high doses (1% in the diet for 121 wk). However, this substance is apparently non-genotoxic in a range of test systems. Anethole is metabolized in the rat along three primary pathways, one of which is epoxidation across the double bond of the side-chain. The epoxides of a number of the alkenylbenzene family of food flavours, of which anethole is a member, are putative genotoxins, being bacterial mutagens but not mammalian carcinogens. The authors have previously shown that the cytotoxicity of anethole is enhanced when the cellular epoxide defence mechanisms of conjugation with reduced glutathione and hydration by cytosolic epoxide hydrolase are severely compromised. They now report, however, that modulation of epoxide metabolism in cultured cells by the same mechanisms fails to induce unscheduled DNA synthesis (UDS) by anethole nor was there a UDS response in hepatocytes of female rats dosed with anethole in vivo. The epoxide of anethole was synthesized for the first time in this investigation and tested directly. As expected, it was markedly cytotoxic but not genotoxic. Anethole epoxide has chemical characteristics that differ from those of other structurally similar epoxides being labile to hydrolysis in aqueous media at physiological pH and temperature. This gives greater relevance to tests of its genotoxicity after formation within the hepatocyte rather than by adding the epoxide extracellularly to the culture medium. The direct and indirect demonstration of the lack of induction of UDS by anethole epoxide provides further support for the hypothesis that marginal hepatocarcinogenicity observed in female rats given 1% anethole in the diet for 121 wk was not initiated by a genotoxic event.

Allylbenzene Derivatives↗
PubMed1996

Telephone follow-up after discharge from the hospital: does it make a difference?

Two systems of telephone follow-up of discharged patients were compared in this 3-month study. All medical and surgical patients on five nursing units of one acute care institution were included, yielding a sample of over 1,400 patients. One group of patients was called 2 to 3 days after discharge; another group received a brochure describing a nurse-run telephone service they could call. A third group of patients received no intervention. More than 90% of patients who were called had questions about self-care and recovery at home. Only nine patients initiated calls to the nurse telephone service. The three groups did not differ in patient satisfaction with health education or readmission rates within 30 days of discharge. This study suggests that patients have continued health education needs after discharge but are unlikely to actively seek needed information from a hospital-based telephone service.

Follow-Up Studies↗
PubMed1996

Immunochemical detection of covalently modified protein adducts in livers of rats treated with methyleugenol.

Methyleugenol is an allylbenzene food flavoring which has been shown to form DNA and protein adducts, and to cause hepatotoxicity and carcinogenicity in rodents. In order to investigate the nature of the protein adducts, specific antisera were raised by immunizing rabbits with conjugates prepared by coupling 1'-acetoxymethyleugenol, or its acidic congener 3,4-dimethoxycinnamic acid, to rabbit serum albumin (RSA). These polyclonal antisera were shown by enzyme linked immunosorbent assay (ELISA) to contain antibodies which recognized the 3,4-dimethoxyphenyl ring portion of methyleugenol. Analysis of livers from rats given methyleugenol i.p. for 5 days, at doses between 10 and 300 mg/kg/day, revealed dose-dependent formation of novel protein adducts which were recognized by the antisera. The adducts were detected by ELISA and by immunoblotting and were concentrated in the microsomal fraction, and were shown in inhibition studies to be derived from methyleugenol. A 44 kDa adduct was the only protein adduct detected in livers of rats given low loses of methyleugenol (10 or 30 mg/kg/day) and was the major adduct detected in rats given high doses of the compound (100 and 300 mg/kg/day). This adduct was solubilized when microsomal fractions were extracted using 0.1 M sodium carbonate, implying that it is a peripheral membrane protein. A pattern of protein adducts which mirrored the in vivo situation was generated when rat hepatocytes were incubated with 1'-hydroxymethyleugenol in vitro, but could not be reproduced in experiments undertaken using liver microsomes or postmitochondrial supernatants. These findings imply that generation of protein adducts in livers of rats given methyleugenol in vivo proceeds via the 1'-hydroxy metabolite and requires crucial cofactors, and/or structural features, which are present in intact hepatocytes but not in broken cell preparations and which remain to be defined.

Animals↗
PubMed1996

Needs and program strengths: perceptions of hospice volunteers.

A state-wide survey was conducted of highly effective hospice volunteers who were questioned about their motivations for becoming a volunteer, training experience and needs, and reasons for continuing in the volunteer role. Needs identified included having a volunteer support group, on-going training opportunities, and opportunities for getting to know other volunteers better. Excellent training, belief in the hospice mission, the relationship with staff, feeling valued, and personal fulfillment were strengths and motivations to continue as a hospice volunteer. Findings from the study will be helpful to hospice staff who recruit, train, and support volunteers.

Adult↗
PubMed1996

Novel alterations in CDK1/cyclin B1 kinase complex formation occur during the acquisition of a polyploid DNA content.

The pathways that regulate the S-phase events associated with the control of DNA replication are poorly understood. The bone marrow megakaryocytes are unique in that they leave the diploid (2C) state to differentiate, synthesizing 4 to 64 times the normal DNA content within a single nucleus, a process known as endomitosis. Human erythroleukemia (HEL) cells model this process, becoming polyploid during phorbol diester-induced megakaryocyte differentiation. The mitotic arrest occurring in these polyploid cells involves novel alterations in the cdk1/cyclin B1 complex: a marked reduction in cdk1 protein levels, and an elevated and sustained expression of cyclin B1. Endomitotic cells thus lack cdk1/cyclin B1-associated H1-histone kinase activity. Constitutive over-expression of cdk1 in endomitotic cells failed to re-initiate normal mitotic events even though cdk1 was present in a 10-fold excess. This was due to an inability of cyclin-B1 to physically associate with cdk1. Nonetheless, endomitotic cyclin B1 possesses immunoprecipitable H1-histone kinase activity, and specifically translocates to the nucleus. We conclude that mitosis is abrogated during endomitosis due to the absence of cdk1 and the failure to form M-phase promoting factor, resulting in a disassociation of mitosis from the completion of S-phase. Further studies on cyclin and its interacting proteins should be informative in understanding endomitosis and cell cycle control.

CDC2 Protein Kinase↗
PubMed1996

Desflurane and isoflurane increase lumbar cerebrospinal fluid pressure in normocapnic patients undergoing transsphenoidal hypophysectomy.

BACKGROUND: Rapid emergence from anesthesia makes desflurane an attractive choice as an anesthetic for patients having neurosurgery. However, the data on the effect of desflurane on intracranial pressure in humans are still limited and inconclusive. The authors hypothesized that isoflurane and desflurane increase intracranial pressure compared with propofol. METHODS: Anesthesia was induced with intravenous fentanyl and propofol in 30 patients having transsphenoidal hypophysectomy with no evidence of mass effect, and it was maintained with 70% nitrous oxide in oxygen and a continuous 100 micrograms.kg-2.min-1 infusion of propofol. Patients were assigned to three groups randomized to receive only continued propofol infusion (n = 10), desflurane (n = 10), or isoflurane (n = 10) for 20 min. During the 20-min study period, each patient in the desflurane and isoflurane groups received, in random order, two concentrations (0.5 minimum alveolar concentration [MAC] and 1.0 MAC end-tidal) of desflurane or isoflurane for 10 min each. Lumbar cerebrospinal fluid (CSF) pressure, blood pressure, heart rate, and anesthetic concentrations were monitored continuously. RESULTS: Lumbar CSF pressure increased significantly in all patients receiving desflurane or isoflurane. Lumbar CSF pressure increased by 5 +/- 3 mmHg at 1-MAC concentrations of desflurane and by 4 +/- 2 mmHg at 1-MAC concentrations of isoflurane. Cerebral perfusion pressure decreased by 12 +/- 10 mmHg at 1-MAC concentrations of desflurane and by 15 +/- 10 mmHg at 1-MAC concentrations of isoflurane. Heart rate increased by 7 +/- 9 bpm with 0.5 MAC desflurane and by 8 +/- 7 bpm with 1.0 MAC desflurane, and by 5 +/- 11 bpm with 1.0 MAC isoflurane. Systolic blood pressure decreased in all but the patients receiving 1.0 MAC desflurane. To maintain blood pressure within predetermined limits, phenylephrine was administered to six of ten patients in the isoflurane group (range, 25 to 600 micrograms), two of ten patients in the desflurane group (range, 200 to 500 micrograms), and in no patients in the propofol group. Lumbar CSF pressure, heart rate, and systolic blood pressure did not change in the propofol group. CONCLUSION: Desflurane and isoflurane, at 0.5 and 1.0 MAC, increase lumbar CSF pressure.

Adult↗
PubMed1996

Hyperthyroidism during pregnancy: nursing care issues.

Untreated hyperthyroidism during pregnancy is associated with a high incidence of maternal and fetal complications. The perinatal nurse needs knowledge of the pathophysiology of this condition to implement a care plan. Antithyroid medications are used to restore the patient's normal thyroid function. Ongoing evaluation of clinical and laboratory data assists the nurse in recognizing the development and implementation of interventions for complications, such as thyroid crisis and heart failure, in the pregnant patient.

Adult↗
PubMed1996

Pathways of metabolism of [1'-14C]-trans-anethole in the rat and mouse.

This study describes the metabolic fate of trans-4'-methoxyprop-[1-14C]enylbenzene, the natural flavor compound trans-anethole, in rats and mice given single doses of 250 mg/kg body weight. In both rats and mice, an essentially quantitative (> 95% of dose) recovery of 14C was obtained with the majority in the 0-24 hr urine. Separation and identification of 18 urinary anethole metabolites were achieved by radio-HPLC, chemical derivatization, and GC/ MS. Anethole undergoes three primary oxidation pathways-O-demethylation, omega-side chain oxidation, and side chain epoxidation-followed by a variety of secondary pathways of oxidation and hydration, the products of which are extensively conjugated with sulfate, glucuronic acid, glycine, and glutathione. A novel major metabolite has been characterized in the rat, apparently originating from conjugation of the epoxide with glutathione, namely S-[1-(4'-methoxyphenyl)-2-hydroxypropane]-N-acetylcysteine. These metabolites are discussed in terms of the pathways responsible for and the toxicological consequences of their formation.

Acetylcysteine↗
PubMed1996

Cryopreservation of rat and mouse hepatocytes. I. Comparative viability studies.

We have compared the viability of cultures of cryopreserved (CP) rat and mouse hepatocytes with fresh cells with respect to their attachment efficiency, uptake of neutral red (NR), 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carbo xyanilide xyanilide inner salt (XTT) metabolism, and ability to synthesize new proteins. Total recovery of rat hepatocytes after cryopreservation was 42.1 +/- 18.0%, with high viability (82.3 +/- 7.8%, as determined by trypan blue exclusion). These cells had significantly lower attachment efficiencies than fresh cells over 72 hr in culture. Viability of CP rat hepatocyte cultures was lower than fresh cell cultures, but was constant throughout 72 hr (approximately 68%). Total recovery of CP mouse hepatocytes (postthaw viability = 85.4 +/- 6.8%) was 53.6 +/- 14.7%. CP and fresh mouse hepatocyte cultures had similar attachment efficiencies and viabilities. NR uptake by CP rat hepatocyte cultures was significantly higher than in fresh cells at 48 and 72 hr after plating (400% and 810% of fresh cells, respectively). In contrast, CP mouse hepatocytes, which did not detach significantly in culture, took up NR to the same extent as fresh cells. The rate of NR uptake into rat and mouse hepatocytes, cultured for 24 hr, was unaltered by cryo-preservation. XTT metabolism by hepatocytes from either species was not affected by cryopreservation. Protein synthesis over 72 hr, as measured by incorporation of [3H]leucine, was lower in CP cultures than in fresh cells (CP rat hepatocyte protein synthetic activity was 32.3 +/- 6.8% of fresh, and CP mouse hepatocyte protein synthetic activity was 49.0 +/- 10.1% of fresh). Protein synthesis did not alter over 72 hr culture.

Animals↗
PubMed1996

Cryopreservation of rat and mouse hepatocytes. II. Assessment of metabolic capacity using testosterone metabolism.

Cryopreservation of hepatocytes is widely used, but to validate the use of cryopreserved (CP) hepatocytes in metabolic studies, CP cells must compare favorably with fresh cell activities. We have assessed the metabolic capacity of fresh and CP rat and mouse hepatocytes in primary culture. Total cytochrome P450 (P450) contents and metabolism of testosterone were measured up to 72 hr in culture. At 0 hr, total P approximately 450 in CP rat hepatocytes was 102.5 +/- 32.8 pmol/10(6) cells, compared with fresh rat hepatocytes that had 148.2 +/- 75.7 pmol/10(6) cells. The P450 contents of mouse hepatocytes were also unaltered by cryopreservation (176.7 +/- 56.0 pmol/ 10(6) fresh cells; 196.4 +/- 59.9 pmol/10(6) CP cells). There were no significant differences in the total P450 contents of fresh and CP rat and mouse cell cultures with time over 72 hr in culture. The overall metabolism of testosterone was lower in CP suspensions than in freshly isolated hepatocytes. When CP hepatocyte suspensions were permeabilized (with digitonin) and incubated with NADPH and ATP, testosterone metabolism was significantly increased. Testosterone hydroxylase activities (16 alpha-, 6 beta-, 2 alpha-, and 7 alpha-hydroxylase) were equivalent in fresh and CP rat hepatocytes over 72 hr in culture. There was a marked and sustained loss of 6 beta-hydroxylase activity in CP mouse hepatocyte cultures, compared with fresh hepatocytes throughout 72 hr in culture (436.9 +/- 118.0 pmol/min/10(6) cells and 37.3 +/- 41.0 pmol/min/10(6) cells at 72 hr in fresh and CP mouse hepatocytes, respectively). The total metabolism of testosterone was, however, unaffected because 16 alpha-hydroxylase activity increased in CP mouse hepatocytes (475.4 +/- 80.8 pmol/min/10(6) CP cells, compared with 148.7 +/- 39.4 pmol/min/10(6) fresh cells).

Adenosine Triphosphate↗
PubMed1995

Interleukin-1 alpha upregulates tumor necrosis factor receptors expressed by a human bone marrow stromal cell strain: implications for cytokine redundancy and synergy.

To explore the biochemical and physiologic basis of the overlapping effects of interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF-alpha) on myeloid cytokine production, we have studied the dynamics of granulocyte colony-stimulating factor (G-CSF) and granulocyte-monocyte colony-stimulating factor (GM-CSF) production as well as IL-1 receptor and TNF receptor expression in a clonally derived bone marrow stromal cell strain (CDCL). IL-1 alpha and TNF alpha act in a synergistic manner to stimulate G-CSF and GM-CSF production by CDCL, resulting in an increase in CSF secretion that is 250-fold greater than that observed with either cytokine alone. This synergism in protein secretion is paralleled by synergistic increases the steady-state level of GM- and G-CSF mRNA, with supra-additive levels achieved by 24 hours. Coincident with this synergistic induction of myeloid CSFs, treatment of CDCL cells with IL-1 alpha induces a 300% increase in the expression of TNF receptors. IL-1 alpha induction of TNF receptors reaches a peak after 6 hours and gradually returns to baseline level by 24 hours. IL-1 alpha does not affect TNF receptor ligand binding affinity. A kinetic study comparing IL-1/TNF synergistic induction of growth factor secretion with IL-1 alpha induction of TNF receptors shows that these events occur in parallel. In contrast with the induction of TNF receptors by IL-1 alpha, treatment with TNF alpha has no effect on either the number of IL-1 receptors expressed by CDCL cells or IL-1 receptor ligand binding affinity. Brief treatment of IL-1 alpha/TNF alpha-stimulated CDCL cells with cycloheximide before receptor induction reduces the synergistic increase in growth factor mRNA by 40% to 60% compared with cells not treated with CHX. Taken together, these results raise the possibility that IL-1 alpha cross-induction of TNF receptors may contribute to the biochemical mechanisms underlying the synergistic stimulation of G-CSF and GM-CSF production by IL-1 alpha and TNF alpha.

Antigens, CD↗