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Biomedical subjects

G White

Publications and source records attributed to G White.

At least 109 records · Page 6Linked to original sources
PubMed1993

Ethanol action on excitatory amino acid activated ion channels.

The effects of ethanol on excitatory amino acid activated ion channels were investigated using patch-clamp recording methods. Intoxicating concentrations of ethanol (5-50 mM) inhibited ion current activated by the glutamate receptor agonist N-methyl-D-aspartate (NMDA) in a concentration-dependent manner (IC50 = 30 mM). The intoxicating potency of different alcohols was correlated with their potency for inhibiting NMDA-activated current, suggesting that alcohol-induced inhibition of NMDA channel function may contribute to the neural and cognitive impairments associated with intoxication. Analysis of mechanism suggests that ethanol inhibits NMDA-activated current by altering gating of the channel, rather than by affecting channel conductance, ion permeance or regulatory sites on the channel. Anesthetic concentrations of ethanol (> 50 mM) produced a concentration-dependent inhibition of kainate- and quisqualate-activated currents (IC50 = 220 mM), suggesting that this inhibition may contribute to the general anesthetic effects of ethanol. This hypothesis is supported by the observations that the general anesthetic agents, trichloroethanol (the active metabolite of chloral hydrate), pentobarbital and halothane, all inhibit kainate- and quisqualate-activated currents.

Animals↗
PubMed1993

Straight segmental versus bifurcation grafts for repair of abdominal aortic aneurysm.

The decision of two surgical teams to repair an infrarenal aneurysm with a straight or bifurcation graft in 94 patients was investigated. Nine patients had an emergency operation and the two who died within 30 days of surgery (mortality rate 2%) had a ruptured aneurysm. Of 88 patients with follow-up data of at least 1 year (mean 3.5 years), 46 received bifurcation grafts and 42 tube grafts. The mean transverse diameter of the aneurysm on ultrasonography was 6.5 cm for straight and 6.1 cm for bifurcation grafts. The mean duration of operation was longer for bifurcation than straight grafts (4.2 versus 3.3 h, P < 0.05) and intraoperative blood loss greater for the former (2292 versus 1350 ml, P < 0.05). The incidences of late complications for the two grafts were not different. The only secondary aneurysm repair was a staged procedure on a descending thoracic aortic aneurysm. No postoperative iliac aneurysms were detected by routine physical examination and pelvic ultrasonography in patients receiving straight grafts. Even though there was no preselection of patients by disease status, one surgical team relying on preoperative arteriography successfully replaced 28 of 39 aneurysms (72%) with tube grafts while the other team using primarily intraoperative assessment placed straight grafts in only 14 of 49 patients (29%). In conclusion, straight grafts can be implanted in approximately two-thirds of patients undergoing aortic aneurysm repair with significantly less operating time and blood loss and without increase in the incidence of late iliac occlusion or dilatation.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗
PubMed1993

Retrospective study comparing the pathophysiology of antibiotic-treated and untreated Escherichia coli- and Staphylococcus aureus-infused baboons.

Escherichia coli and Staphylococcus aureus are the most common pathogens encountered in septic shock. This is a descriptive study in which the pathophysiologic response to infusions of LD100 concentrations of E. coli and S. aureus are staged and compared. Equivalent concentrations of both organisms were infused over a 2 hr period into antibiotic-treated and untreated animals with the following results: 1) The apparent clearance of E. coli was less than that of S. aureus over the 2-hr infusion period, but far greater during the next 8 hr in both antibiotic-treated and untreated animals. Thus the clearance of E. coli fits a one-compartment (intravascular), and that of S. aureus fits a two-compartment (intra- and extravascular) model. 2) The intensity of the cardiovascular, temperature, and metabolic response to E. coli was greater, whereas that of the disseminated intravascular coagulant (DIC) response to S. aureus was greater. We conclude, therefore, that the response to E. coli consists of four stages with no invasion and colonization of tissues, whereas the response to S. aureus consists of two stages with invasion and colonization of tissues.

Animals↗
PubMed1993

Transluminal placement of a prosthetic graft-stent device for treatment of subclavian artery aneurysm.

A 78-year-old man was seen with an expanding 5 cm false aneurysm of the right subclavian artery. This was treated by an intraluminal graft-stent device introduced through the brachial artery via a 16 F sheath. The graft was constructed from two polytetrafluoroethylene patches of 0.4 mm thickness and anchored in the subclavian artery by an 8 mm stainless steel stent. The procedure was monitored by an image intensifier. Completion arteriography and postoperative duplex scanning confirmed normal flow through the subclavian artery with no communication between the lumen and the aneurysmal sac. The patient recovered without complication.

Aged↗
PubMed1992

Breast cancer survival among women under age 50: is mammography detrimental?

Great uncertainty exists about the benefit of detecting breast cancer by mammography in women under 50 years of age. We have reviewed the survival of patients aged 49 years or less whose cancers were detected by mammography alone. 117 women under the age of 50 years were diagnosed with breast cancer between 1978 and 1991 based only on an abnormal mammogram. Ductal carcinoma in-situ (DCIS) was found in 47 (40%) of these women, whilst 70 (60%) had infiltrating ductal or infiltrating lobular carcinomas. During the same interval, 928 women in this age group presented with palpable breast cancer. DCIS was diagnosed in 82 (9%) of these women, whilst 846 (91%) had infiltrating carcinoma. Among the infiltrating cancers detected by mammography alone, 50% were stage I, whilst only 30% of the women with palpable cancers were stage I. Five-year survival for all mammographically detected cancer patients was 95%, whereas for women with palpable cancers the survival was 74% (p < 0.00005). If DCIS is not included, the corresponding survivals are 91% for mammographically detected infiltrating cancers and 72% for palpable infiltrating cancers. Only 1 woman who died among those with palpable cancer had had a mammogram before diagnosis. Our data contradict the suggestion that women under 50 are put at a survival disadvantage by undergoing mammography. We believe that investigators who have reported negative results in this age group must examine other causes for their results.

Actuarial Analysis↗
PubMed1992

Pharmacokinetic properties of recombinant factor VIII compared with a monoclonally purified concentrate (Hemofil M). The Recombinate Study Group.

A recombinant FVIII preparation, Recombinate, was compared with a high-purity plasma-derived concentrate, Hemofil M, in 47 hemophilia A patients in a cross-over evaluation of pharmacokinetic properties. The recombinant material showed a significantly lower clearance, volume of distribution, and higher in vivo recovery, but a similar half-life to the plasma-based product. In a comparison with reported data from other standard concentrates, the recombinant preparation exhibited potentially better pharmacokinetic properties in that its clearance was slower and its half-life was longer. We conclude that the recombinant DNA method of preparation does not adversely affect the biological and pharmacological characteristics of the factor VIII molecule.

Adolescent↗
PubMed1992

1,9-Dideoxyforskolin does not mimic all cAMP and protein kinase A independent effects of forskolin on GABA activated ion currents in adult rat sensory neurons.

The effect of forskolin on GABAA receptor activated events has been the subject of recent investigations, the conclusions of which are conflicting. Forskolin can reduce current amplitude and increase the rate of decay of current activated by 100 microM GABA and these effects are not mimicked by 1,9-dideoxyforskolin (Tehrani et al., Synapse, 4 (1989) 126-131). On the other hand, both forskolin and 1,9-dideoxyforskolin inhibit 36Cl- flux induced by lower concentrations of muscimol (Heuschneider and Schwartz, Proc. Natl. Acad. Sci. USA, 86 (1989) 2938-2942). Using the whole-cell patch clamp technique to measure GABA activated current in dorsal root ganglion neurons that were freshly isolated from adult rats, we have confirmed the finding of Tehrani et al. (Synapse, 4 (1989) 126-131) using 100 microM GABA; however, the effects of forskolin that were not mimicked by 1,9-dideoxyforskolin were not blocked by the kinase inhibitor H-7 (50 microM). In contrast, at lower concentrations of GABA (10-20 microM), both forskolin and 1,9-dideoxyforskolin increased the decay rate of GABA activated current. In addition, all effects of forskolin occurred within 200 ms of application of forskolin and the effects were not blocked or occluded by H-7, 10 microM cAMP, or the active subunit of protein kinase A. We conclude that: (1) 1,9-dideoxyforskolin is not a reliable indicator of forskolin specificity in this system because its effects are dependent upon GABA concentration; and (2) the most prominent effects of forskolin on amplitude and decay time course of GABA activated ion current are not mediated by cAMP or protein kinase A (PKA).

Animals↗
PubMed1992

Heterogeneity in EC50 and nH of GABAA receptors on dorsal root ganglion neurons freshly isolated from adult rats.

GABA activates a Cl- current through the GABAA receptor/ionophore complex that influences excitability of neurons. Studies using expression of cloned cDNAs coding for different GABAA receptor/ionophore subunits suggest that the EC50 and Hill coefficient for GABA are influenced by subunit composition. However, no direct evidence for such heterogeneity has been reported for vertebrate neurons. I have investigated the heterogeneity of EC50 and Hill coefficients (nH) of isolated dorsal root ganglion neurons using the whole-cell patch clamp technique. The EC50 for GABA varied from 26 to 107 microM among neurons. nH calculated from the logistic equation varied from 1.18 to 2.0. A negative correlation was found between the EC50 and nH (r = -0.81). Both nH and EC50 differed between some cells. However, in some instances, nH differed between cells while EC50 values were similar, and in other cells, EC50 values differed and nH was similar. In addition, when cells were categorized according to action potential shape, the EC50 and Hill coefficients differed among cell types in some instances and were similar in other instances. These findings demonstrate that different pharmacological profiles for GABA can be observed in adult mammalian neurons. Selective distribution of such pharmacological subtypes of GABAA receptors may contribute to control of neuronal excitability.

Animals↗
PubMed1992

Effects of nerve growth factor on TTX- and capsaicin-sensitivity in adult rat sensory neurons.

We have investigated the effects of nerve growth factor (NGF, 2.5 ng/ml for 1-2 weeks) on enriched adult rat dorsal root ganglion (DRG) neurons maintained in cell culture in defined media. Whole-cell recordings in cells cultured in the absence and presence of NGF revealed no significant difference in resting membrane potential and input resistance. However, the threshold for spike generation was significantly lower in untreated cells than in treated cells; -25 +/- 1.1 mV vs -19 +/- 2.2 mV, respectively. The sensitivity of the Na+ spike to tetrodotoxin (TTX, 1 microM) was different in cells cultured in the absence or presence of NGF. For example, spikes were abolished by TTX in 100% of untreated cells, while in NGF-treated cells the spike was abolished in only 41% of the neurons. Chemosensitivity of DRG neurons was also different in the absence and presence of NGF. For example, the percent of neurons in which a current activated by 8-methyl-N-vanillyl-6-nonenamide (capsaicin, 500 nM) was detected, increased from 18% in untreated cells to 55% in NGF-treated cells. NGF did not influence the number of cells surviving. The results indicate that NGF can regulate TTX and capsaicin sensitivity in these adult rat sensory neurons. Our experimental protocol indicates that this effect is not mediated by a factor in the serum or released from non-neuronal cells.

Action Potentials↗
PubMed1992

pp39mos is associated with p34cdc2 kinase in c-mosxe-transformed NIH 3T3 cells.

We investigated the possible interactions between pp39mos and p34cdc2 kinase in NIH 3T3 cells transformed by c-mosxe. pp39mos is coprecipitated with p34cdc2 when using either anti-PSTAIR antibody or p13suc1-Sepharose beads. Likewise, p34cdc2 is coprecipitated with pp39mos when using anti-mos antibody. However, pp39mos was not present in histone H1 kinase-active p34cdc2 complexes precipitated with anti-p34cdc2 C-terminal peptide antibody even during metaphase of the cell cycle. The molar ratio of p34 to pp39mos in the p13suc1 complex is approximately 2:1. Consistent with the tight association between pp39mos and tubulin, tubulin was also present in equivalent amounts with pp39mos and p34 in the p13suc1 complex. This pp39mos-p34cdc2-tubulin complex may be important in transformation by the mos oncogene.

3T3 Cells↗
PubMed1992

Calcified suture material in the breast after radiation therapy.

Of 335 women who underwent lumpectomy and radiation therapy for breast cancer, 42 subsequently developed calcifications. Particles typical of calcified suture material were identified in 21 of the 42 women (50%). No obvious calcified suture material was found in approximately 1,140 women of 38,000 (3%) who had undergone mammography after they had previously undergone breast biopsy for a benign lesion and thus had not undergone radiation therapy. Calcified suture material rarely develops in the nonirradiated breast, but it is common after radiation therapy and should not be confused with recurrent breast cancer. These calcifications are likely the result of delayed resorption of catgut sutures, which provide a matrix on which calcium can precipitate in a suitable local environment.

Breast Neoplasms↗
PubMed1992

The source of pulsatile secretion of progesterone during the human follicular phase.

This study was designed to establish the normal pattern of serum progesterone and the origin of its secretion during the follicular phase of the normal menstrual cycle. In the first study, 12 normal women were studied on 3 occasions each at different times during a single follicular phase. Serum samples were collected every 10 min over 8 h, for 6 h before and 2 h after an injection of naloxone (5 mg iv). The mean serum progesterone remained constant (0.9 nmol/L) across the follicular phase until just before ovulation; individual subjects showed pulsatility of progesterone (1-6 pulses/6 h) but there was no relationship of this to LH pulsatility and no variation of progesterone pulsatility across the follicular phase. Naloxone caused an increase in the mean serum progesterone in the early follicular phase to 1.9 +/- 0.7 nmol/L and in the mid and late follicular phase to 2.1 +/- 0.7 nmol/L and 3.4 +/- 2.5 nmol/L, respectively. The second study was performed to assess the contribution of the residual corpus luteum and the developing follicle to the pulsatile secretion of progesterone. Seven anovulatory women with low levels of serum LH and absent LH pulsatility were studied before and after clomiphene (100 mg/day for 5 days) by collecting blood samples every 15 min for 6 h before GnRH (10 mg iv) and for 2 h afterwards. The anovulatory women had comparable mean serum concentration of progesterone (0.9 +/- 0.5 nmol/L) to normal women and similar frequency of progesterone pulsatility (2.1 +/- 1.1 pulses/6 h). After administration of clomiphene, there was no significant change in progesterone pulsatility (1.7 +/- 1.0 pulses/6 h) despite a substantial increase in LH pulsatility (from none to 3.0 +/- 1.0 pulses/6 h). There was no significant increase in serum progesterone after clomiphene or GnRH which both caused a substantial increase in serum LH. The third study involved eight normal women studied before and after treatment with dexamethasone (2 mg/day for 2 days) to assess the adrenal component of progesterone secretion. Blood samples were collected every 10 min for 6 h before and 2 h after naloxone (5 mg iv). Dexamethasone reduced serum progesterone to below assay sensitivity (less than 0.2 nmol/L) and obliterated progesterone pulsatility. The increase in serum progesterone and cortisol induced by naloxone was blocked by dexamethasone; the naloxone-induced rise of serum LH was not affected by dexamethasone. We conclude that neither the preceding corpus luteum nor the developing follicle are important contributors to the serum concentration of progesterone during the normal follicular phase.(ABSTRACT TRUNCATED AT 400 WORDS)

Activity Cycles↗
PubMed1992

GABA- and glutamate-gated ion channels as molecular sites of alcohol and anesthetic action.

The evidence presented above indicates that GABA- and glutamate-activated ion channels are molecular sites of alcohol and anesthetic action. In view of the important role that these channels play in CNS excitability, it seems likely that the actions of alcohol and anesthetics on these channels contribute significantly to the behavioral effects of these agents. Although the behavioral effects of alcohol and anesthetics may well result from a combination of actions on different ion channels and other molecular sites in the CNS, it is of interest to consider whether the actions of these agents on particular types of ion channels may contribute to particular behavioral effects. In this regard, it should be noted that benzodiazepines potentiate GABAA responses, but do not produce intoxication or general anesthesia in their clinical dose range. Benzodiazepines are widely used clinically, primarily for their anxiolytic actions (26), suggesting that the potentiation of GABAA responses by ethanol and barbiturates may contribute to the anxiolytic effects of these agents. Since kainate and quisqualate channels mediate fast excitatory transmission in the CNS, inhibition of kainate and quisqualate receptor-activated responses would be expected to result in general CNS depression. This suggests that inhibition of kainate and quisqualate receptor-mediated responses may contribute to the general anesthetic effects of ethanol, trichloroethanol and barbiturates. NMDA channels are thought to mediate complex excitatory neural phenomena and cognitive function. In view of this, the observation that ethanol inhibits NMDA receptor-mediated responses over the concentration range that produces intoxication and the correlation between the potency of different alcohols for inhibiting NMDA-activated current and their potency for producing intoxication suggest that ethanol-induced inhibition of NMDA receptor-mediated responses may contribute to the intoxicating effects of ethanol. Although these speculations are no doubt oversimplifications, the recognition that GABA- and glutamate-gated ion channels are molecular sites of alcohol and anesthetic action provides a basis for investigating the molecular mechanisms involved in the action of these agents and the behavioral significance of those actions.

Alcohols↗
PubMed1991

Construction, expression and characterization of humanized antibodies directed against the human alpha/beta T cell receptor.

Completely humanized antibodies with specificity for the human alpha/beta TCR have been produced by genetic engineering. The L and H chain V region exons encoding the murine mAb BMA 031 CD regions and human EU framework regions were synthesized and replaced into previously isolated genomic fragments. These fragments were inserted into mammalian expression vectors containing the human kappa and gamma 1 C region exons. Two variants were constructed each containing selected BMA 031 amino acids within the human frameworks. The humanized genes were transfected into Sp2/0 hybridoma cells by electroporation and transfectomas secreting humanized antibody were isolated. Levels of antibody expression up to 7 pg/cell/24 h were obtained. The humanized antibody, BMA 031-EUCIV2, competed poorly with murine BMA 031 for binding to T cells. BMA 031-EUCIV3, however, bound specifically to T cells and competed effectively with both the murine BMA 031 antibody and a previously constructed chimeric BMA 031 antibody for binding to these cells. The relative affinity of BMA 031-EUCIV3 was about 2.5 times lower than BMA 031. The ability to promote antibody dependent cell-mediated cytolysis was significantly enhanced with the engineered antibodies as compared to murine BMA 031. Humanized BMA 031 is a clinically relevant, genetically engineered antibody with potential uses in transplantation, graft vs host disease, and autoimmunity.

Amino Acid Sequence↗
PubMed1991

TTX-sensitive action potentials and excitability of adult rat sensory neurons cultured in serum- and exogenous nerve growth factor-free medium.

The excitability of adult rat dorsal root ganglion (DRG) neurons cultured in the absence of serum and exogenously added nerve growth factor (NGF) was studied. Current-clamp recordings revealed the presence of tetrodotoxin (TTX)-sensitive action potentials. Voltage-clamp recordings demonstrated the presence of both inward and outward currents. The inward Na+ current had a maximal amplitude near -10 mV and was completely blocked by TTX. A sustained Ca2+ inward current and a slowly activating outward K+ current were also observed. TTX-sensitive and TTX-resistant action potentials have been observed in previous studies in DRG neurons cultured in the presence of serum. By contrast, in the study reported here, only TTX-sensitive action potentials and Na+ currents were found in the neurons cultured in the absence of serum and nerve growth factor.

Action Potentials↗