Large-scale chromosome sorting.
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Animals↗
Biomedical subjects
J C Martin
Publications and source records attributed to J C Martin.
Concepts of veterinary practice in wild mammals.
At the beginning of this article, we described the challenge faced by wildlife veterinarians in extrapolating treatment regimens and finding data bases of physiologic variables with which to assess health or depth of anesthesia in wild mammals. For example, we might wish to administer injectable ivermectin to a 75-kg deer and a 75-g squirrel for treatment of intestinal nematodes. An effective dose of ivermectin for the 75-kg deer is 0.2 mg/kg SC, and for the 75 g (0.075 kg) squirrel is 1.3 mg/kg SC. Given the squirrel dose (1.3 mg/kg), the deer could be made very ill or even killed by the treatment; whereas given the deer dose (0.2 mg/kg), the squirrel would not receive enough ivermectin to achieve a therapeutic level. This is the reason for allometric scaling of drug doses. Scaling doses allometrically is an arithmetic procedure that is more precise than trying to extrapolate doses between animals of diverse body sizes (such as the ermine and the wolverine) and between species that have different core body temperature set points (such as marsupial and placental mammals). For many years, in human and veterinary medicine, practitioners have allometrically scaled doses of potentially toxic chemotherapeutic agents using either (1) mg or micrograms drug/M2 body surface area or (2) mg or micrograms of drug/SMEC. Allometric calculations give results that are much more predictable and take into consideration substantial differences in body size and core body temperature.
Anesthesia, Inhalation↗
Dietary fat induces changes in factor VII coagulant activity through effects on plasma free stearic acid concentration.
Previous studies have demonstrated activation of the contact system of coagulation and an increase in factor VII coagulant activity (VIIc) when citrated plasma is incubated in the presence of micellar stearate. The products of contact activation, factors XIIa and IXa, were responsible in this system for the activation of factor VII, thereby increasing factor VIIc. To obtain evidence that these in vitro interactions also operate in vivo, factor VIIc was examined in relation to plasma free fatty acid concentrations in five healthy individuals during the consumption of isocaloric high-saturated fat, high-unsaturated fat, and low-fat diets, each taken for 4 weeks in random order and separated by intervals of 12 weeks. For all but the final 3 days of each phase, subjects selected appropriate foods from prepared lists to meet the dietary requirements. Experimental diets of predetermined fat content and composition were fed on days 26 through 28 in each phase. Fat supplied on average 62% of energy in two of the experimental diets and less than 20% of energy in the third. On the final day of each dietary phase, the concentrations of the various free fatty acids and factor VIIc were measured before breakfast and at three 150-minute intervals thereafter. Plasma factor VIIc was, respectively, 6.5% and 13.1% of standard higher on the unsaturated and saturated fat diets than on the low-fat diet. Furthermore, the plasma concentration of stearic acid was strongly associated with factor VIIc (r = .58; P < .0001), and this relation remained significant (P = .003) after allowance for the plasma concentrations of palmitic, oleic, and linoleic acids.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Recent developments concerning accrediting agencies in postsecondary education.
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Accreditation↗
[Erythromelalgia: a familial case. Discussion on the role of mercury].
Erythromelalgia is an acrosyndrome characterized by paroxysmal manifestations associating erythema, local sensations of warmth and pain which improve with exposure to cold. Childhood forms, exceptional and usually primary, are quite severe and particularly resistant to treatment. The search for a causal agent is most often negative and the pathogenesis remains to be determined. We report a case of erythromelalgia observed in a 4-year-old girl, her father and her younger sister. This case was particular due to an association with mercury poisoning. The symptomatology was improved after different therapeutic attempts including Clomipramide and, particularly effective, rerigerating socks (D(r) Comet, CNES, Toulouse). In the literature we were unable to find any case of erythromelalgia related to mercury poisoning. The cases of familial erythromelalgia reported suggest X-linked dominant transmission. Finally, this case demonstrated the difficulties in diagnosing and treating erythromelalgia, especially in the child.
Acrodermatitis↗
Factor VII-deficient substrate plasmas depleted of protein C raise the sensitivity of the factor VII bio-assay to activated factor VII: an international study.
Plasma from healthy individuals, pregnant women and patients on warfarin were distributed to 3 laboratories supporting major cardiovascular surveys (Northwick Park, Muenster and Houston) for assay of factor VII coagulant activity (VIIc) with their own bio-assays. The mean VIIc in 147 samples agreed to within 1% of standard in Northwick Park and Houston, but was 14% of standard lower in Muenster owing to its more potent standard. In samples with an increased VIIc the Northwick Park assay gave a higher result than the other assays owing to its increased responsiveness to activated factor VII (VIIa). Thus when VIIa concentrations were determined directly with a clotting assay which utilises a soluble recombinant tissue factor, the increase in VIIc with increase in VIIa was considerably greater with the Northwick Park assay than the Muenster assay. This feature of the Northwick Park assay was traced to the virtual absence of protein C in its substrate plasma. Factor Va appears rate-limiting for the coagulant expression of VIIa in test plasma. If the thrombotic response to release of tissue factor is determined by the circulating concentration of VIIa, then the Northwick Park factor VII bio-assay may be preferable to other bio-assays currently employed to estimate risk of acute coronary events.
Adult↗
Synthesis and antiviral activity of 2'-substituted 9-[2-(phosphonomethoxy)ethyl]guanine analogues.
A series of 2'-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG, 1) have been synthesized and evaluated in vitro for anti-human immunodeficiency virus (HIV) activity in the XTT assay and for anti-herpes activity in the plaque reduction assay. It has been observed that the anti-HIV activity of these derivatives depends on the size and the nature of the substituent as well as the chirality at the 2'-position of PMEG. In addition, these compounds generally demonstrated greater activity against HIV than herpes viruses. The most interesting analogues which emerged from these studies are (R)-2'-(azidomethyl)-PMEG [(R)-5] and (R)-2'-vinyl-PMEG [(R)-11]. The former showed anti-HIV activity with an IC50 of 5 microM and a cytotoxicity (CC50) greater than 1.4 mM in CEM cells. The latter has an IC50 of 13 microM for anti-HIV activity and a CC50 of greater than 1.6 mM. Furthermore, we have demonstrated that replacement of the guanine base of these 2'-substituted PMEG analogues with cytosine drastically reduces anti-HIV and anti-herpes activity.
Antineoplastic Agents↗
Current concepts in antisense drug design.
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Animals↗
Rapid sizing of individual fluorescently stained DNA fragments by flow cytometry.
Large, fluorescently stained restriction fragments of lambda phage DNA are sized by passing individual fragments through a focused continuous wave laser beam in an ultrasensitive flow cytometer at a rate of 60 fragments per second. The size of the fluorescence burst emitted by each stained DNA fragment, as it passes through the laser beam, is measured in one millisecond. One hundred sixty four seconds of fluorescence burst data allow linear sizing of DNA with an accuracy of better than two percent over a range of 10 to 50 kbp. This corresponds to analyzing less than 1 pg of DNA. Sizing of DNA fragments by this approach is much faster, requires much less DNA, and can potentially analyze large fragments with better resolution and accuracy than with gel-based electrophoresis.
Bacteriophage lambda↗
Triacylglycerol structure of human colostrum and mature milk.
Because triacylglycerol (TAG) structure influences the metabolic fate of its component fatty acids, we have examined human colostrum and mature milk TAG with particular attention to the location of the very long chain polyunsaturated fatty acid on the glycerol backbone. The analysis was based on the formation of various diacylglycerol species from human milk TAG upon chemical (Grignard degradation) or enzymatic degradation. The structure of the TAG was subsequently deduced from data obtained by gas chromatographic analysis of the fatty acid methyl esters in the diacylglycerol subfractions. The highly specific TAG structure observed was identical in mature milk and colostrum. The three major fatty acids (oleic, palmitic and linoleic acids) each showed a specific preference for a particular position within milk TAG: oleic acid for the sn-1 position, palmitic acid for the sn-2 position and linoleic acid for the sn-3 position. Linoleic and alpha-linolenic acids exhibited the same pattern of distribution and they were both found primarily in the sn-3 (50%) and sn-1 (30%) positions. Their longer chain analogs, arachidonic and docosahexaenoic acids, were located in the sn-2 and sn-3 positions. These results show that polyunsaturated fatty acids are distributed within the TAG molecule of human milk in a highly specific fashion, and that in the first month of lactation the maturation of the mammary gland does not affect the milk TAG structure.
Colostrum↗
The use of the holmium laser for temporomandibular joint arthroscopic surgery.
Temporomandibular joint arthroscopic surgery was performed on 86 human joints with a holmium yttrium aluminum garnet (YAG) laser (Coherent, Palo Alto, CA) passed through a quartz fiber. The wattage and number of pulses needed for tissue response, the temperature produced, and the average time needed for this surgery are presented. Holmium laser technology applied to the temporomandibular joint appears to be an effective, safe, and efficient modality.
Arthroscopy↗
Dependence of human milk essential fatty acids on adipose stores during lactation.
The relationships between essential fatty acid (EFA) composition of colostrum, mature milk, and white adipose tissue (WAT) were examined on days 5 and 30 postpartum in 24 healthy French mothers. Fatty acid composition was assessed by capillary gas chromatography. In WAT, the proportion of individual polyunsaturated fatty acids (PUFAs) did not change during lactation and was greater (18:2n-6) or lower (18:3n-3, long-chain PUFAs) than values found in colostrum or mature milk (P < 0.04). The 18:2n-6 content and the ratio of 18:3n-3 to 18:2n-6 correlated between WAT and colostrum (r = 0.52 and r = 0.57, respectively) or mature milk (r = 0.64 and r = 0.65, respectively). These relationships agree with an expected qualitative effect of WAT fatty acid composition on interindividual variability of milk parent EFA content. The decrease in the long-chain PUFA content observed from colostrum to mature milk and the concomitant occurrence of a precursor-product relationship between the linoleate and its long-chain PUFA are consistent with the mobilization of a preformed long-chain PUFA pool during early lactation.
Adipose Tissue↗
The relationship between factor VII coagulant activity and factor XII activation induced in plasma by endogenous or exogenously added contact surface.
The contribution of various enzymes in the activation of factor VII, determined from the increase in factor VII coagulant activity (VIIc), was investigated following the exposure of citrated plasma to low temperature. The contact system of coagulation was initiated either by the contact surface present in certain plasmas (i.e. plasma from women in late pregnancy) or by micellar stearate added to plasma diluted with an equal volume of buffer (plasma from normal healthy subjects or from women in late pregnancy). With either of the contact surfaces, increase of VIIc and the concentration of enzymes derived from factor XII (XIIa) depended on the potency of the contact surface. The stearate-induced VIIc in diluted plasmas from women in late pregnancy or from normal subjects was inhibited by 60-70% in the presence of anti-factor IX monoclonal antibody. VIIc was not increased in XII-deficient plasma following the addition of stearate. The addition of purified human factor XII to this plasma restored the increase in VIIc and the activation of factor XII. In factor IX-deficient plasma, the stearate-induced increase in VIIc was only 38% of that seen in normal plasma and was restored by the addition of purified factor IX. Similarly in factor XI-deficient plasma, the stearate-induced increase in VIIc and the factor XII activation were 48% and 69% of that found in normal plasma. The addition of EDTA (2 mM) did not alter the extent of factor XII activation induced by contact surface, but it did inhibit the rise in VIIc. It is concluded that in the presence of contact surface the activation of factor XII and the sequential activation of factor XI and of factor IX results in the activation of factor VII. Activated factor IX is responsible for the major part of the factor VII activation whereas the rest may be through the direct activation by XIIa.
Antibodies, Monoclonal↗
Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase.
Peroxynitrite (ONOO-), the reaction product of superoxide (O2-) and nitric oxide (NO), may be a major cytotoxic agent produced during inflammation, sepsis, and ischemia/reperfusion. Bovine Cu,Zn superoxide dismutase reacted with peroxynitrite to form a stable yellow protein-bound adduct identified as nitrotyrosine. The uv-visible spectrum of the peroxynitrite-modified superoxide dismutase was highly pH dependent, exhibiting a peak at 438 nm at alkaline pH that shifts to 356 nm at acidic pH. An equivalent uv-visible spectrum was obtained by Cu,Zn superoxide dismutase treated with tetranitromethane. The Raman spectrum of authentic nitrotyrosine was contained in the spectrum of peroxynitrite-modified Cu,Zn superoxide dismutase. The reaction was specific for peroxynitrite because no significant amounts of nitrotyrosine were formed with nitric oxide (NO), nitrogen dioxide (NO2), nitrite (NO2-), or nitrate (NO3-). Removal of the copper from the Cu,Zn superoxide dismutase prevented formation of nitrotyrosine by peroxynitrite. The mechanism appears to involve peroxynitrite initially reacting with the active site copper to form an intermediate with the reactivity of nitronium ion (NO2+), which then nitrates tyrosine on a second molecule of superoxide dismutase. In the absence of exogenous phenolics, the rate of nitration of tyrosine followed second-order kinetics with respect to Cu,Zn superoxide dismutase concentration, proceeding at a rate of 1.0 +/- 0.1 M-1.s-1. Peroxynitrite-mediated nitration of tyrosine was also observed with the Mn and Fe superoxide dismutases as well as other copper-containing proteins.
Animals↗
Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite.
Superoxide dismutase and Fe3+EDTA catalyzed the nitration by peroxynitrite (ONOO-) of a wide range of phenolics including tyrosine in proteins. Nitration was not mediated by a free radical mechanism because hydroxyl radical scavengers did not reduce either superoxide dismutase or Fe3+EDTA-catalyzed nitration and nitrogen dioxide was not a significant product from either catalyst. Rather, metal ions appear to catalyze the heterolytic cleavage of peroxynitrite to form a nitronium-like species (NO2+). The calculated energy for separating peroxynitrous acid into hydroxide ion and nitronium ion is 13 kcal.mol-1 at pH 7.0. Fe3+EDTA catalyzed nitration with an activation energy of 12 kcal.mol-1 at a rate of 5700 M-1.s-1 at 37 degrees C and pH 7.5. The reaction rate of peroxynitrite with bovine Cu,Zn superoxide dismutase was 10(5) M-1.s-1 at low superoxide dismutase concentrations, but the rate of nitration became independent of superoxide dismutase concentration above 10 microM with only 9% of added peroxynitrite yielding nitrophenol. We propose that peroxynitrite anion is more stable in the cis conformation, whereas only a higher energy species in the trans conformation can fit in the active site of Cu,Zn superoxide dismutase. At high superoxide dismutase concentrations, phenolic nitration may be limited by the rate of isomerization from the cis to trans conformations of peroxynitrite as well as by competing pathways for peroxynitrite decomposition. In contrast, Fe3+EDTA appears to react directly with the cis anion, resulting in greater nitration yields.
Animals↗
Synthesis and antiviral activity of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine.
A number of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG, 1) have been synthesized and tested in vitro for anti-herpes and anti-human immunodeficiency virus (HIV) activity. Among these analogues, (R)-2'-methyl-PMEG [(R)-3] and 2',2'-dimethyl-PMEG (7) demonstrated potent anti-HIV activity in the XTT assay with EC50 values of 1.0 and 2.6 microM, respectively. The corresponding (S)-2'-methyl-PMEG [(S)-3] was found to be less potent against HIV. In addition, the (R) and (S) enantiomers of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine (HPMPG, 8) were prepared for comparison of biological activity, and shown to be active and equipotent against herpesviruses, but inactive against HIV.
Antiviral Agents↗
Hageman factor and risk of myocardial infarction in middle-aged men.
In order to evaluate whether Hageman factor (XII) is increased in survivors of myocardial infarction and whether this in turn influences factor VII coagulant activity (VIIc), we examined the coagulation and lipoprotein profiles in 82 subjects, 51 of whom had a definite history of myocardial infarction and 31 healthy volunteers invited from a local general practice register for a cardiovascular screen. Both serum cholesterol (P = 0.03) and plasma fibrinogen levels (P = 0.02) were significantly elevated in cases compared with controls. There were no significant differences in coagulant activities, and in particular factor XII concentration was not significantly different between groups. Furthermore, in 47 of the subjects, 28 of whom had a history of myocardial infarction, a more detailed analysis, including measurement of VIIc after overnight incubation of plasma at 4 degrees C, was undertaken. Approximately half the subjects in either group showed some evidence of activation, though history of myocardial infarction was not in itself a significant predictor of this. All measures of XII concentration related positively to VIIc after cold activation, the strongest being the measure of amidolytic activity following activation of factor XII (XIIAm) (r = 0.5, P < 0.01). In addition, XIIa, a measure of activity due to enzymes derived from factor XII, related strongly to many of the measured lipoprotein variables, particularly VLDL cholesterol and triglycerides, supporting the hypothesis that negatively charged molecules such as free fatty acids on larger lipoprotein particles provide the contact surface necessary to activate factor XII. The findings confirm the importance of this alternative pathway in leading to activation of factor VII.
Aged↗
Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine.
9-(2-Phosphonylmethoxyethyl)adenine (PMEA; 1) was acylated with chloromethyl pivalate to afford bis(pivaloyloxymethyl) PMEA (2). The ester prodrug demonstrated enhanced in vitro potency against HSV-2 greater than 150-fold higher than the parent compound. The antiviral activity of 2 was 50-fold better than PMEA against HSV-1, and equipotent against HIV and HCMV. The toxicity of 2 was studied in both resting and growing cells.
Adenine↗