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Biomedical subjects

G Wright

Publications and source records attributed to G Wright.

At least 145 records · Page 8Linked to original sources
PubMed1991

Conversion of pig pancreas phospholipase A2 by protein engineering into enzyme active against Escherichia coli treated with the bactericidal/permeability-increasing protein.

Phospholipases A2 (PLA-2) are conserved enzymes that can vary widely in their activity toward certain biological targets. Activity of PLA-2 toward Escherichia coli treated with the bactericidal/permeability-increasing protein (BPI) of granulocytes has been detected only in "Group II" PLA-2 (lacking Cys11-Cys77) and correlates with overall basicity and the presence of a cluster of basic amino acids within a variable surface region near the NH2 terminus (including residues 6, 7, 10, 11, and 15). We now show that of five pancreatic PLA-2 ("Group I" enzymes) tested from different species of mammals, the human enzyme that is most basic both globally (pI 8.7) and locally (Arg-6, Lys-7, and Lys-10) is active toward BPI-treated E. coli (approximately 1-2% activity of the most active Group II PLA-2) whereas the other four PLA-2 are essentially inactive (less than 0.1%). The cDNA of the pig pancreatic PLA-2 (pI 6.4; Arg-6, Ser-7, Lys-10) has been modified by site-specific mutagenesis and the wild-type and mutant PLA-2 have been expressed in and purified from either E. coli or Saccharomyces cerevisiae to determine more precisely the structural determinants of PLA-2 activity toward BPI-treated E. coli. The single substitution of lysine (or arginine) for Ser-7 transformed the pig pancreatic PLA-2 into an active enzyme toward BPI-treated E. coli possessing 25-50% the activity of the human PLA-2. Additional modifications to increase global basicity (increase in net charge up to +4) caused a further (up to 2-fold) increase in activity. All mutant PLA-2 still containing Ser-7 possessed little or no activity toward BPI-treated E. coli. Changes in activity toward BPI-treated E. coli were accompanied by parallel changes in enzyme binding to this target. In contrast, substitution of lysine (or arginine) for Ser-7 caused little or no alteration of enzyme activity toward either autoclaved E. coli or egg yolk lipoproteins indicating no major effects on the catalytic properties of the PLA-2. This study demonstrates directly the role of NH2-terminal basic residues in the action of PLA-2 on BPI-treated E. coli and suggests that these properties mainly facilitate PLA-2 binding to this biological target.

Animals↗
PubMed1991

Focal neuronal migration disorders and intractable partial epilepsy: a study of 30 patients.

We studied 30 patients with partial epilepsy and a radiological or pathological diagnosis of localized neuronal migration disorders, with a view to surgical treatment. Eight patients had identifiable prenatal etiological factors. The frequency of complex partial, partial motor, and secondarily generalized seizures was approximately 70% each. Drop attacks were present in 27%: Their presence usually correlated with a lesion involving the central region. Partial motor or generalized convulsive status epilepticus occurred in 30%, and was most frequently associated with extensive structural abnormalities involving two or more lobes. A full-scale intelligence quotient of less than 80 was found in 44%. Magnetic resonance imaging (MRI) was superior to computed tomography for identification of the dysplastic cortical lesions. In one third, MRI showed only subcortical abnormalities. It did not allow distinction between true pachygyria, focal cortical dysplasia, or the forme fruste of tuberous sclerosis. The epileptogenic area was usually more extensive than the lesion; it was multilobar in more than 70% of patients. Of 26 surgically treated patients, a histological diagnosis of the type of neuronal migration disorder was possible in 22: 12 had focal cortical dysplasia and 10 the forme fruste of tuberous sclerosis. In the remaining 4, no definite histological diagnosis was made, since the maximally abnormal tissue could not be examined. In the latter, and in the 4 nonoperated patients, the diagnosis of neuronal migration disorder was based on imaging findings. The presence of the forme fruste of tuberous sclerosis correlated with delayed psychomotor development and more extensive epileptogenic areas.

Adolescent↗
PubMed1991

Partial dissection of the zona pellucida of frozen-thawed human embryos may enhance blastocyst hatching, implantation, and pregnancy rates.

The rate of successful implantation after replacement of frozen-thawed embryos in in vitro fertilization is commonly only 5% to 10% per embryo. A limiting factor may be inability of otherwise viable embryos to be released from the intact zonae pellucidae. Culture conditions and/or cryopreservation in in vitro fertilization may affect the zona and impair blastocyst hatching. Therefore opening of the zona by partial slicing by means of micromanipulation before replacement of early cleaved embryos may improve chances of eventual hatching (referred to as assisted hatching). In 65 thawed embryo replacement cycles methyl-prednisolone and antibiotics were given for 4 days mid cycle. Assisted hatching was performed in 32 cycles, with 33 cycles left as controls. Patient's age, infertility, cycle supplementation, and number of thawed and replaced embryos did not differ significantly between the two groups. Rates of viable embryonic implantation were 16% (10/63) and 9% (6/64) in the assisted hatching and control groups, respectively. Group sizes need approximately to double before this trend toward improved implantation with the use of assisted hatching reaches statistical significance.

Adult↗
PubMed1991

5-HT1b receptors in an animal model of depression.

After exposure to a 0.8 mA course of uncontrollable shocks, Sprague-Dawley rats can be differentiated into two distinct groups defined in term of their performance in a shock escape paradigm. Learned helpless (LH) rats do not learn to escape a controllable shock while non-helpless (NLH) rats learn this response as quickly as naive controls (NC) rats do. The current experiments were designed to extend our studies of 5-HT receptors in these three groups of rats. The major finding in the present study concerned post-synaptic 5-HT receptor effects in the cortex, hippocampus, septum and hypothalamus of LH rats. These included an up regulation of 5-HT1b receptors in the cortex, hippocampus and septum in LH rats. In contrast, 5-HT1b receptors in the hypothalamus of LH rats were down-regulated. These results implicate serotonergic mechanisms in the behavioral deficit caused by uncontrollable shock with a limbic-hypothalamic circuit serving as a center for adaptation to stress.

Animals↗
PubMed1991

Cancer of the cervix--old and young, now and then.

A study of two 5-year periods, 1960-1964 and 1982-1986, in Queensland is made. Changing patterns of preinvasive and invasive cervical carcinoma in the world literature are discussed. The age of presentation, stage, histology, and results in Queensland for cervical carcinoma are analyzed. There are over 500 patients in each quinquennium. While the total female population has increased 86%, the maximum increase is in patients under 35 years and over 65. There has been a 50% decrease in the incidence of cervical carcinoma, but a doubling under the age of 30. The stage at diagnosis has markedly improved with 88% stage Ib in the young as opposed to 50% formerly. Late-stage disease remains a problem of the aged. The mortality in both time spans increases with age. Histologic patterns show an increase in nonsquamous patterns and increased mortality in the rare patterns. We have no evidence of the emergence of a rapidly progressive carcinoma in the young. Papanicolaou smear and education programs appear to be preventing cervical carcinoma and allowing diagnosis of the disease at an earlier stage and age. This is reflected in a decrease in mortality from 9.6 per 100,000 (1960-1964) to 4 per 100,000 (1982-1986).

Adult↗
PubMed1991

Stimulation cycles suppressed with gonadotropin-releasing hormone analog yield accelerated embryos.

A retrospective study was performed to assess embryonic development and morphology in 71 patients whose follicular stimulation was regulated after down regulation with a gonadotropin-releasing hormone analog, leuprolide acetate. The embryos were compared with those from 66 patients who did not receive agonists and who were treated during the same period. A separate group of thawed embryos cryopreserved after down regulation in 21 patients was compared with embryos frozen after conventional stimulation during the same period from 21 other patients. Eleven morphological criteria were assessed in the fresh embryos, and analyses did not reveal any differences between the groups studied. However, the rate of development of embryos obtained during down-regulated cycles was significantly higher than that of embryos developing in conventional stimulation cycles. Although no significant morphological differences could be shown between the groups of cryopreserved embryos, there was a decreased incidence of implantation of embryos from patients who were exposed to analogs. It is suggested that embryos from down-regulated cycles should be cryopreserved earlier to correct for their accelerated development.

Clomiphene↗
PubMed1991

Interaction of GTP derivatives with cellular and oncogenic ras-p21 proteins.

A series of N2-substituted guanosine 5'-triphosphates was synthesized from the corresponding nucleosides. The nucleosides were prepared by treatment of N2-substituted guanines with tetra-O-acetylribose under conditions which maximized the yield of the 9-beta-guanosine isomers. These nucleotides and several sugar- and base-modified analogues of GTP were tested for their ability to bind to cellular and oncogenic forms of the GTP/GDP binding proteins, Ha-ras-p21. Several N2-substituted GTPs showed affinities higher than that of GDP itself, and the N2-[p-(n-butyl)phenyl] derivative bound to the oncogenic mutant, Leu-61 p21, twice as strongly as to the cellular protein. Changes in relative affinities of the nucleotides are discussed with reference to reported crystallographic structures of p21.

Genes, ras↗
PubMed1991

High level expression of active human alpha-1-antitrypsin in the milk of transgenic sheep.

We describe the generation of five sheep transgenic for a fusion of the ovine beta-lactoglobulin gene promotor to the human alpha 1-antitrypsin (h alpha 1AT) genomic sequences. Four of these animals are female and one male. Analysis of the expression of h alpha 1AT in the milk of three of these females shows that all express the human protein at levels greater than 1 gram per liter. In one case initial levels exceeded 60 grams per liter and stabilized at approximately 35 grams per liter as lactation progressed. Human alpha 1AT purified from the milk of these animals appears to be fully N-glycosylated and has a biological activity indistinguishable from human plasma-derived material.

Animals↗
PubMed1991

Expression of a polymorphic epithelial mucin antigen defined by the monoclonal antibody BC2 in ovarian carcinoma. Use of the BC2 antibody for the detection of micrometastases.

The BC2 monoclonal antibody, which binds to an epitope on the peptide backbone of polymorphic epithelial mucin, was tested immunohistochemically for reactivity with epithelial ovarian carcinoma. This epitope was expressed in 90 of 91 malignant ovarian tumors; in 88% of these, more than 50% of the tumor cells expressed the epitope. In 94% of the positive tumors, the epitope was expressed on the cell membrane; in 56%, cytoplasmic expression was evident; and in 39%, secreted extracellular antigen was detected. Differences were not clearly discernible between dissimilar histotypes with respect to the percentage of cells expressing antigen and antigen localization. Thirteen of 19 benign ovarian cystadenomas also expressed the epitope, but staining was weak and restricted to the luminal surface of the cell membrane. A blind retrospective immunohistochemical analysis of all second-look laparotomy biopsy specimens from 20 patients also was performed. All four patients in whom microscopic disease was detected by standard pathologic assessment had BC2-positive metastases. Of seven patients in whom recurrent disease subsequently developed despite negative pathologic findings, four had biopsy specimens containing BC2 antigen-positive adenocarcinoma-like cells. Of the nine patients with negative results on operation and no recurrence, one had biopsy specimens containing BC2 antigen-positive adenocarcinoma-like cells. Mesothelial cells, although typically negative, expressed the epitope in one biopsy specimen, necessitating caution in the interpretation of positive cells. The BC2 antibody is reactive with most epithelial ovarian carcinomas and appears to be a useful tool for the detection of micrometastases.

Antibodies, Monoclonal↗
PubMed1991

Effects of vasoactive drugs upon haemodynamic power and input impedance in normal rats.

STUDY OBJECTIVE: The objectives were (a) to describe the effects of vasoactive drugs in normal rats upon cardiovascular function assessed by computing aortic haemodynamic power and input impedance, each separated into their component parts, and (b) to study the relationship between left ventricular pulsatile power output and the vascular impedance. DESIGN: Haemodynamic power and input impedance were computed from measurements of aortic blood pressure and flow in normal rats. The rats were then given an infusion of a vasoconstrictor drug (methoxamine) followed by a vasodilator drug (hydralazine) in order to study the effects of changes in vascular impedance upon haemodynamic power. EXPERIMENTAL MATERIAL: The measurements were made on pentobarbitone anaesthetised male Wistar rats of approximately 400 g body weight (10 infused with Hartmann's solution as controls and 10 infused with the drugs). MEASUREMENTS AND MAIN RESULTS: Aortic total haemodynamic power was between 9.96 mW and 10.37 mW during the control period and reached a maximum of 11.36 mW during the methoxamine infusion, but this difference was not statistically significant. It then decreased significantly to 4.32 mW by the end of the hydralazine infusion. Pulsatile power was only 0.32(SEM 0.08) mW (2.8% of the total power) in the control state and decreased to 0.12(0.1) mW (1.7%) during the methoxamine infusion, but increased to 0.59(0.15) mW (12.5%) by the end of the hydralazine infusion. The vascular effects were complex and involved all four of the input impedance parameters--peripheral resistance, characteristic resistance, arterial compliance, and inertance. Reflex responses of the vascular wall were apparent as temporal changes in characteristic resistance and arterial compliance. CONCLUSIONS: Changes in cardiovascular function can be described by computing haemodynamic power and input impedance and then separating these into their component parts. Administration of the vasoactive drugs affected left ventricular mean and pulsatile power output and all four components of the input impedance. The frequency distribution of left ventricular pulsatile power output may be matched to the vascular impedance in order to optimise tissue perfusion.

Animals↗
PubMed1991

Routine application of partial zona dissection for male factor infertility.

Partial zona dissection (PZD) increases the chances of fertilization by improving the access of spermatozoa to the perivitelline space (PVS) helping those spermatozoa unable to penetrate the zona pellucida (ZP) and possibly those poorly able to penetrate the oolemma. Problems arise in assessing semen to decide which parameters might indicate defects of this nature. PZD, by circumventing the ZP, may also increase the rate of polyspermy, especially in infertility where ZP and oolemmal penetration are not defective. Given these drawbacks, we performed PZD as routine treatment for male infertility in 70 in-vitro fertilization cycles. In three different groups, PZD proved to be either effective, ineffective or unnecessary. In the first group of 35 cycles, fertilization was 23% with initial PZD and 33% with PZD reinsemination (36% and 41% polyspermy respectively). No fertilization occurred following conventional insemination (CONV). Four pregnancies occurred in this group. In a second group of 19 cycles, fertilization did not occur with either PZD or CONV. In the final group of 16 cycles, fertilization was similar following both PZD and CONV, but polyspermy was 48% in the PZD category. Transfer of mixed PZD and CONV embryos in this group yielded 10 pregnancies. Assessment of all patient and seminal profiles, and those in an oligozoospermic subcategory, revealed no parameters of relevance to success or failure with PZD. However, one subgroup in the group of total failure to fertilize did have a significantly lower percentage of normal morphology (P less than 0.005), suggesting that degree of teratozoospermia may be a prognosticator of success using PZD.

Female↗
PubMed1991

Is what you see what you get? Breast specimen handling re-visited.

Specimen radiography is already established as an essential adjunct to excisional biopsy of mammographically detected abnormalities. Two methods of specimen sectioning following the initial specimen radiograph are described. The techniques were devised to identify the lesion accurately in the specimen for subsequent pathological analysis. They have been tailored to suit the differing facilities at two Breast Screening Centres. The methods highlight the desirability of a cooperative multidisciplinary approach to the management of breast disease. They underline the importance of radiological localization of the lesion; not only for the surgeon, but also for the pathologist.

Biopsy↗
PubMed1991

Modulation of [3H]paroxetine binding to the 5-hydroxytryptamine uptake site in an animal model of depression.

The effects of learned helplessness on the 5-hydroxytryptamine (5-HT) uptake site were studied in rats using [3H]paroxetine binding. This ligand was chosen because it was demonstrated to label directly the 5-HT uptake site whereas the [3H]imipramine binding site has been demonstrated to be heterogeneous in nature. Moreover, [3H]imipramine appears to bind to a presynaptic recognition site different from the uptake site. Exposure to uncontrollable shock training and testing resulted in an overall increase in [3H]paroxetine binding in all the groups studied [nonhelpless (NLH), learned helpless (LH), spontaneously helpless (SPLH)] as compared to naive controls (NC). However, the increase in [3H]paroxetine binding was significantly higher in the LH and SPLH groups. The maximum number of [3H]paroxetine binding sites in the rat hippocampus was increased significantly in learned helpless rats (LH and SPLH) at day 4 and day 30 after the shock escape test as compared to NC and NLH rats. By contrast, in the rat hypothalamus the maximum number of [3H]paroxetine binding sites was reduced significantly in the LH rats as compared to naive controls and NLH rats during the same time course. There was no change in [3H]paroxetine binding sites in any other brain regions examined in LH, NLH, and NC rats. The results suggest that a hippocampal hypothalamic connection might play a role in the serotonergic mediation of learned helpless behavior.

Animals↗
PubMed1991

Use of leeches in a case of severe periorbital haematoma.

A case of severe penetrating eye injury and resulting periorbital haematoma is described. Leeches applied to the eyelids enabled examination of the globe to be carried out and improved the surgical approach. Leeches provide a speedy and efficient means of reducing a periorbital haematoma.

Animals↗
PubMed1991

Use-dependent decline in rat aorta sensitivity to contraction by potassium.

Aortic rings excised from rats at 12 weeks of age showed a decrease in responsiveness during repeated contraction by increasing potassium concentration. By comparison, aortic rings obtained from rats at 22 and 26 weeks exhibited less loss or an increase in responsiveness to high potassium concentration during repeated contraction. The decrease in responsiveness to potassium in aortae of young rats was not due to the extended interval of incubation of these tissue in vitro. Aortic rings incubated without stimulation for 4 h following a reference contraction showed no change in contractile response to potassium. However, the magnitude of loss in responsiveness to potassium did appear to be related to the potassium concentration and the length of time the tissues were exposed to the high potassium solutions. Contraction of the tissue at 60 versus 30 mM KCl or extending the interval in depolarizing solution from 15 to 60 min significantly enhanced the decline in tissue responsiveness to potassium. The interruption of a series of potassium-induced contractions by exposure of the tissue to contractile (serotonin, norepinephrine) or relaxant (acetylcholine, isoproterenol) stimuli had no effect on the loss in responsiveness to potassium. However, injection of the calcium channel agonist, Bay K 8644, into the incubation media restored responsiveness to potassium. Concentration-response curves indicated that both sensitivity and the maximal response to potassium were reduced in aortic rings repeatedly contracted with potassium.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals.

We determined plasma methocarbamol concentrations over 24 h following a 1.5 g methocarbamol dose (off-dialysis day) to 8 chronic haemodialysis patients and compared these results to those from 17 healthy male volunteers. The harmonic mean elimination half-life was similar between the two groups, 1.24 and 1.14 h, respectively. tmax and the weight-adjusted Cmax were 1.1 h and 27.0 mg.m-1 for haemodialysis patients and 1.1 and 23.1 mg.l-1 for normals. Relative systemic availability was assessed by comparing weight-normalized AUC x k10 products. These results indicate no significant differences with respect to methocarbamol absorption, with the relative systemic availability in patients being 113%. These data suggest that absorption and elimination of methocarbamol is similar between normal subjects and patients undergoing maintenance haemodialysis.

Chromatography, High Pressure Liquid↗