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Biomedical subjects

M Mackay

Publications and source records attributed to M Mackay.

At least 37 records · Page 2Linked to original sources
PubMed1996

Chromosomal localization in mouse and human of the vasoactive intestinal peptide receptor type 2 gene: a possible contributor to the holoprosencephaly 3 phenotype.

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) have been shown to act on a wide range of tissue and cell types, both in the central nervous system and in the periphery. Two distinct receptors for VIP, the VIP receptor type 1 (VIPR1) and the VIP receptor type 2 (VIPR2), have recently been cloned, each of which binds PACAP and VIP with equal affinity. We report here the chromosomal mapping of the human and mouse VIPR2 genes by fluorescence in situ hybridization. The VIPR2 gene maps to the human chromosomal region 7q36.3 and to the F2 region of mouse chromosome 12. Our localization of the human gene places it in the region where the locus for the craniofacial defect holoprosencephaly type 3 (HPE3) maps. Further mapping experiments, carried out on cell lines derived from patients with HPE or HPE microforms and associated 7q deletions, have led us to redefine the distal extent of the HPE3 minimal critical region, originally characterized by Gurrieri et al. (1993, Nature Genet. 3: 247-251.) The VIPR2 gene lies within this new HPE3 minimal critical region. Our results suggest that deletion of the VIPR2 gene is not the sole factor responsible for the HPE3 phenotype. However, it is possible that monosomy at the VIPR2 locus may contribute to the phenotype observed in many cases of HPE3.

Animals↗
PubMed1995

The transport of acidic amino acids and their analogues across monolayers of human intestinal absorptive (Caco-2) cells in vitro.

The X-AG system, a sodium-dependent, acidic amino-acid transport system has been implicated in the transport of L-aspartate and L-glutamate across monolayers of human Caco-2 cells, an in vitro model of intestinal absorption. This system, which shares many properties with the L-glutamate carrier present in the human jejunum, is highly saturable (> 95% at 50 microM), vectorial (apical-to-basolateral >> basolateral-to-apical) and sodium-, pH- and temperature-dependent. L-Aspartate was also transported against a 10-fold reverse concentration gradient. These data are consistent with a major (saturable) carrier-mediated pathway superimposed onto a minor non-saturable (diffusional) pathway. The carrier has an absolute sodium-dependence and the Michaelis constants for the sodium-dependent transport component (Km) for L-aspartate and L-glutamate were 56 +/- 3 microM and 65 +/- 6 microM, respectively. Cross-inhibition studies showed that strong interaction with the carrier was limited to close analogues of the natural substrates. Potent inhibitors included L-aspartate, D-aspartate (Ki, 70 microM), L-glutamate (Ki 180 microM) and threo-beta-hydroxy-DL-aspartate (Ki, 55 microM), while partial inhibitors included alpha-methyl-DL-aspartate, D-glutamate, L-asparagine, L-proline and L-alanine. Replacement of the side-chain -COO- group (aspartate) with -SO-3 (L-cysteate, Ki, 65 microM) or -(H)P(O)O- (DL-3-(hydroxyphosphoryl)alanine, Ki, 60 microM) maintained strong interaction with the carrier while -As(O)(OH)O- (DL-3-arsonoalanine, Ki, 1100 microM) and -P(O)(OH)O- (DL-3-phosphonoalanine, Ki, 3270 microM) were much more weakly bound, with the larger, but probably less ionised, arsono analogue being more tightly bound than the phosphono compound. The corresponding analogues of glutamate (homologous extension of the methylene chain) showed negligible interaction. We conclude that Caco-2 monolayers are a relevant experimental model for the study of the transport of acidic amino acids and their analogues in man.

Amino Acids, Dicarboxylic↗
PubMed1995

Head injuries in lateral impact collisions.

Individual non-minor injuries (Abbreviated Injury Scale (AIS) > or = 2) to the head that occurred to belted and unbelted drivers and front seat passengers on the stuck side of impacted vehicles were examined. Injury type, injury combination, collision severity in relation to type of injury as well as contact sources were assessed. Forty-eight percent of injuries were moderate in severity (AIS 2). The most common type of injury was the diffuse brain injury, typically marked by a short period of unconsciousness, which occurred in collisions of lower severity than focal brain and skull fracture injuries. One-hundred and five out of 216 (48.6%) of contact sources for all injury types originated from outside the vehicle and such exterior sources were more likely to result in high severity injuries. Thirty percent of injuries resulted from head contacts with other vehicles. The most frequent vehicle interior contact source was the side window glass. Diffuse injuries tended to occur independently of other injury types and were more likely to originate from an interior rather than exterior contact. Preventative measures for head injury reduction in lateral collisions are discussed. Overall, the data show that proposed and present European and U.S. lateral impact test methods do not address many head injury problems such as those included in this study.

Abbreviated Injury Scale↗
PubMed1995

Appropriate frontal barrier tests for belted occupants.

Vehicle damage from frontal impacts was classified and investigated together with injuries sustained by belted front seat occupants. The sample consisted of 1872 frontal crashes from the Midlands of England. Analysis focused on impacts with broad objects that might conceivably be simulated by a barrier test. Two asymmetrical front-end damage patterns were commonly identified, and these gave the greatest rates of non-minor (Abbreviated Injury Scale (AIS) > or = 2) injuries in a range of Estimated Test Speeds from 35 to 52km/h which is the regime of current legislative crash tests. The most injurious type involved oblique damage caused by a substantial overlap of the struck object. The other type was from a small overlap. Objects struck and passenger compartment intrusions were compared. Appropriate asymmetrical and deformable barrier concepts were discussed. Other findings were connected with the future role of full face barriers as used in current tests such as Federal Motor Vehicle Safety Standard 208. Fuller overlaps (> 50%) tended to give more torso injuries rated > or = AIS 2 caused by seat belt loads and, at high speeds (53-79km/h), caused the most fatalities. Full overlaps (100%) rarely resulted in symmetrical intrusion into the passenger compartment.

Acceleration↗
PubMed1995

Airbag deployment and eye perforation by a tobacco pipe.

Airbags have been shown to reduce injuries and save the lives of car occupants in a crash. Like any protection system, airbags potentially introduce some new risks if no appropriate countermeasures are taken. A case of a relatively moderate frontal impact is described where the driver of an airbag-equipped car suffered a severe penetrating eye injury after the airbag deployed. Since the airbag fabric itself was excluded as an injury-producing structure, other objects such as eyeglasses, a wrist-watch, a bracelet, and a large finger ring had to be assessed. The investigation of the car interior as well as the morphologic details of the injuries to the eye and the face revealed that the most likely candidate for the injury was a tobacco pipe, which was probably being held in one hand and was broken apart by the deploying airbag and projected into the face of the driver. This case illustrates the hazard of having any rigid object between the occupant and the deploying airbag. The desirability of warning car occupants of the potential hazards which can result from today's protection systems is also discussed.

Accidents, Traffic↗
PubMed1994

Engineering in accidents: vehicle design and injuries.

This review has touched superficially on the various mechanisms of injuries to the main classes of road-user casualties, and illustrated some of the desirable vehicle design characteristics which can minimize road trauma. There is still much to be gained by better vehicle design. For occupants, enhanced performance from restraint systems, supplementary airbags, better structural integrity and better compatibility between cars and lorries are obvious areas where known solutions are waiting to be applied. For pedestrians there is an extensive literature outlining the characteristics of friendly vehicle exteriors; many current models of cars are exhibiting some of these properties but better agreement on an optimum specification for the car's exterior is still required. For motorcyclists there is the promise of improved leg protection from energy-absorbing fairings although substantial technical debate still surrounds these proposals. For the clinician, a more accurate appreciation of the likely injuries which occur in given collision circumstances can help in diagnosis and treatment. It is for these reasons that some understanding of vehicle design and crash-worthiness is worthwhile.

Accidents, Traffic↗
PubMed1994

Posterior portals for arthroscopic surgery of the knee.

Posterolateral and posteromedial portals are necessary for certain arthroscopic procedures of the knee. Many surgeons hesitate to use portals. A cadaveric study was performed to identify the structures at risk in establishing these portals. These include the saphenous vein and nerve, popliteal vessels, lateral superior and inferior genicular arteries, and peroneal nerve. Two basic techniques can be used to visualize the posterior compartments--from the same side or diagonally across the intracondylar notch. A clinical review of 179 patients in which posterior portals were used showed no serious complications. In three cases there was residual numbness in the distribution of the saphenous nerve and in two cases the saphenous vein was punctured. In three cases, the posterior compartments could not be safely visualized. In 87 cases the posterior compartment was visualized from the ipsilateral side; in the remaining 92 cases we used the contralateral technique placing the arthroscope diagonally across the intracondylar notch.

Arthritis, Rheumatoid↗
PubMed1994

The transport of two iron chelators, desferrioxamine B and L1, across Caco-2 monolayers.

The transport of two iron chelators, desferrioxamine B (DFO) and L1 (1,2-dimethyl-3 hydroxypyridin-4-one) has been studied in vitro using the human adenocarcinoma cell line, Caco-2. The transport of DFO and L1 has also been compared with that of their iron-bound complexes, ferrioxamine (FO) and L1(3)-Fe, respectively. We report an apparent permeability coefficient (Papp) value for DFO of 0.170 x 10(-7) +/- 0.080 cm s-1. The Papp value of L1 was 1.297 x 10(-5) +/- 0.133 cm s-1. The Papp values of their iron bound complexes FO and L1(3)-Fe are 0.230 x 10(-7) +/- 0.065 cm s-1 and 2.356 x 10(-6) +/- 0.365 cm s-1, respectively. We have shown that the transport of DFO and FO is similar in the Caco-2 cell system. The transport of L1, however, is greatly reduced when complexed to iron. The value for total uptake after 60 min for DFO into the Caco-2 cells was 1.49 +/- 0.09 x 10(-3) nmol per filter. The values for total uptake after 60 min for L1 and L1(3)-Fe were 0.37 +/- 0.03 nmol per filter and 0.04 +/- 0.01 nmol per filter, respectively. Our results indicate that the poor oral bioavailability of DFO can be attributed to the low epithelial permeability of the molecule coupled with its size (mol wt 656). In contrast, the oral bioavailability observed with L1 is due to the high lipophilicity and low molecular weight (mol wt 139) of the molecule. We believe that these differences between the two molecules account for L1 being better orally absorbed than DFO.

Biological Transport↗
PubMed1992

Proline uptake by monolayers of human intestinal absorptive (Caco-2) cells in vitro.

Monolayers of the Caco-2 human intestinal cell line exhibit active and passive uptake systems for the imino acid L-proline. The active transport component is saturable and it is responsible for about two thirds of the observed flux over the nanomolar concentration range, at 37 degrees C and pH 7.4. In contrast to L-phenylalanine, specific L-proline uptake has a high degree of sodium dependency and the efficiency of the carrier system is significantly reduced when protein synthesis (cycloheximide), Na+/K(+)-ATPase (ouabain) or cellular metabolism (sodium azide) are inhibited. The expression of the L-proline carrier by Caco-2 cells was under some degree of nutritional control. Glucose deficiency, over the time scale of the experiment, had no effect. The temperature-dependence of the specific uptake process followed the Arrhenius model with an apparent activation energy of 93.5 kJ nmol-1. This pathway also displayed Michaelis-Menten concentration-dependence with a Ksdm of 5.28 mM and a maximal transport flux (Jsdmax) of 835 pmol min-1 (10(6) cells)-1. Although the passive component was unchanged, the pH of the donor phase exerted a profound effect on the active carrier component. Within the physiological pH range a local maximum efficiency was found at pH 7.4 but dramatic increases were noted as pH 5.0 was approached. In competition studies, with 100-fold excess of a second amino acid, strong inhibition of uptake was found with alpha-aminoisobutyric acid, L-alanine and L-serine whereas moderate inhibition was observed with glycine, D-proline and gamma-aminoisobutyric acid. Aromatic and branched amino acids showed weak (L-valine) or no interaction (L-phenylalanine, L-leucine) with the carrier system. These data indicate that the carrier system for the uptake of L-proline has many features in common with the A system for amino acid transport.

Azides↗
PubMed1992

Intracolonic bioavailability of human calcitonin in man.

Human calcitonin (hCT) injected into the lumen of the descending colon of normal human subjects was absorbed within minutes and could be recognized intact in plasma as shown by RIA in combination with reverse-phase HPLC. The absorption was low and variable, with bioavailabilities ranging from 0.01% to 2.7% relative to intravenously administered hCT (area under the concentration-time curve). With intravenous hCT serum calcium was lowered and the fractional urinary excretion of calcium, phosphorus, sodium and chloride was significantly stimulated. With the intracolonic hCT, the fractional urinary excretions of calcium, sodium and chloride were also marginally stimulated relative to intracolonic vehicle (placebo). In conclusion, hCT is absorbed intact from the colon, but the bioavailability is low and highly variable.

Adult↗
PubMed1992

Diverticuloplasty for severe mucosal injury after cricopharyngeal myotomy.

Cricopharyngeal myotomy with either diverticulopexy or diverticulectomy is the recommended therapy for Zenker's diverticulum. Mucosal injury during myotomy is rare and usually can be managed by direct mucosal closure. A technique is described to repair a serious mucosal defect that may occur during cricopharyngeal myotomy.

Aged↗
PubMed1992

Absorption of human calcitonin across the rat colon in vivo.

1. We studied the absorption of human calcitonin across the colon of juvenile female rats in vivo. Both pharmacokinetic and pharmacodynamic parameters were monitored to measure absorption. 2. Intracolonically administered human calcitonin at doses of 0.1-5.0 mg/kg resulted in a dose-dependent reduction in plasma calcium levels. 3. The bioavailability of intracolonically administered human calcitonin at doses of 5.0, 1.0 and 0.1 mg/kg was 0.5%, 0.9% and 0.2%, respectively. 4. Immunohistochemistry showed that human calcitonin transport across the rat colon was rapid and that a significant amount was via a transcellular pathway. 5. We conclude that human calcitonin crosses the gastrointestinal tract of rats in significant amounts and that this demonstrates the feasibility of an oral form for clinical use.

Animals↗
PubMed1992

Colonic absorption of human calcitonin in man.

1. Human calcitonin was administered into the distal colon and by intravenous infusion in eight healthy subjects in an open, fixed sequence, cross-over bioavailability study. 2. Intravenously infused human calcitonin elicited a standard pharmacokinetic profile in eight healthy subjects with a biphasic elimination with half-lives of 10.2 +/- 0.7 min and 37.8 +/- 2.5 min. 3. Colonoscopically administered human calcitonin was absorbed across the distal colonic mucosa in low amounts with a bioavailability of 0.00-0.22%. 4. Absorption from the distal colon was impeded by the presence of faecal material in three of the eight subjects. 5. We conclude that human calcitonin crosses the gastrointestinal epithelium of man. This may demonstrate the feasibility of an oral form for clinical use.

Adult↗
PubMed1991

Reovirus 1 and 3 bind and internalise at the apical surface of intestinal epithelial cells.

Displacement of [125I]reovirus from the surface of L cells by homologous and heterologous reovirus serotypes has indicated the presence of two different receptors. Corresponding experiments with Caco-2 cells and apical membrane vesicles suggest either two different receptors or different affinity of each reovirus serotype for the same receptor. Binding and internalisation of reovirus at the apical surface of Caco-2 cells and apical membrane vesicles has been demonstrated and the implications of this for models of reovirus infectivity in the intestine are discussed.

Animals↗
PubMed1991

Visual curve tracing properties.

Subjects decided whether 2 dots were on the same curve or 2 different curves, and the curvature of the curves or the proximity of other (distractor) curves to the target curve was varied. Response time increased as the arc length of the curve connecting the 2 dots increased, suggesting that the curve was traced to perform the task. Tracing rate was faster for low- than high-curvature contours and was increasingly slower as distractor contours were increasingly proximal to the traced curve. Proximity results were predicted by a model in which response time depends on the ratio of the distance between the dots and the distance between adjacent lines. Curve tracing operations used to integrate information along contours are sensitive to several properties of the contours. The implications of the sensitivity of tracing operations to these curve properties are discussed.

Adult↗
PubMed1991

Isolation and characterisation of clones from the Caco-2 cell line displaying increased taurocholic acid transport.

The Caco-2 cell line has been cloned by the limiting dilution technique. Clones and reclones have been tested for growth characteristics, transepithelial electrical resistance, ability to transport taurocholic acid specifically and morphological homogeneity. Although clones have similar growth patterns to the parental population they display a variety of electrophysiological, biochemical and morphological characteristics. One clone, clone 40, has been characterised in detail and shown to transport significantly higher amounts of taurocholic acid. Moreover, this clone displays morphological homogeneity and is stable with respect to this parameter over an extended time period.

Adenocarcinoma↗