PubMed Health⌕ Search

Biomedical subjects

C A Hawkins

Publications and source records attributed to C A Hawkins.

At least 19 recordsLinked to original sources
PubMed2001

Structural analysis of the binding modes of minor groove ligands comprised of disubstituted benzenes.

Two-dimensional homonuclear NMR was used to characterize synthetic DNA minor groove-binding ligands in complexes with oligonucleotides containing three different A-T binding sites. The three ligands studied have a C(2) axis of symmetry and have the same general structural motif of a central para-substituted benzene ring flanked by two meta-substituted rings, giving the molecules a crescent shape. As with other ligands of this shape, specificity seems to arise from a tight fit in the narrow minor groove of the preferred A-T-rich sequences. We found that these ligands slide between binding subsites, behavior attributed to the fact that all of the amide protons in the ligand backbone cannot hydrogen bond to the minor groove simultaneously.

AT Rich Sequence↗
PubMed2000

Nitrate anaphylaxis.

BACKGROUND: Nitrate and nitrite salts are commonly used to preserve and sustain color in a number of processed meats. To date there have been no described cases of anaphylaxis to either nitrates or nitrites in the literature. OBJECTIVE: We report a patient with anaphylaxis to nitrates and nitrites documented by double-blind, placebo-controlled capsule challenge. METHODS: A 22-year-old previously well male, presented to a tertiary referral center with a 4-year history of recurrent anaphylaxis after eating take-out food. No further episodes occurred while adhering to a strict elimination diet. We performed a double-blind, placebo-controlled capsule challenge both with food substances and starch placebo. These occurred in a hospital setting with full resuscitative procedures available. RESULTS: An acute anaphylactic reaction occurred following a challenge to nitrates and nitrites. Generalized allergic reactions were observed on separate occasions following administration of artificial colorings and metabisulfite. There was a mild urticarial reaction following salicylates. He was placed on a diet free of sulfites, nitrates, nitrites, and low in salicylates and he has had no further reactions. A computer based search of the Medline, Current Contents and EMBASE databases found no previously reported cases of urticaria, angioedema, or anaphylaxis to either nitrates or nitrites. CONCLUSION: The ingestion of processed meats containing nitrate or nitrite salts may be associated with angioedema and anaphylaxis and should be considered when investigating patients with suspected food allergy.

Adult↗
PubMed2000

Immunomodulation therapy in colorectal carcinoma.

There has been much progress in the understanding of the relationship between the immune system and colorectal cancer. This has led to the use of immunomodulatory therapy in the adjuvant and palliative treatment of the condition. Although attempts at the use of non-specific immunomodulation with agents such as levamisole, cimetidine, alpha interferon and Bacillus Calmette-Guerin (BCG) have not produced significant clinical benefits when tested in randomized trials in both the adjuvant setting and for metastatic disease, promising results are being obtained with more specific therapy. Edrecolomab [corrected], a murine monoclonal antibody targeting the 17-1A antigen on malignant colorectal cells has produced a reduction in relapse and mortality rates when used as adjuvant treatment following surgery for Dukes' C colon cancer. Active specific therapy with autologous tumour vaccine administered with BCG has produced similar benefits in Dukes' B cancer. Both 3H1 anti-idiotypic antibody against carcinoembryonic antigen and 105AD7 antibody to gp72 glycoprotein have demonstrated in-vitro and in-vivo immune activation against tumour. Non-randomized studies postulate prolongation of survival using these antibodies in advanced disease. These agents are all currently being tested in randomized studies powered to detect meaningful survival differences and clinical benefit. Immune therapy offers the potential of low toxicity therapy in colorectal cancer and may have a role as an adjunct to conventional chemotherapy.

Adjuvants, Immunologic↗
PubMed2000

ACL injuries in the skeletally immature patient.

Anterior cruciate ligament injuries are becoming increasingly prevalent in a younger, more athletic population. These injuries require aggressive management given the poor natural history with regard to progressive meniscal damage and advanced degenerative changes. In general, strict nonoperative management has been associated with failure in the individual committed to return to an active lifestyle. As a result a general algorithm can be expressed as follows: 1. Activity limitations and bracing are initially used for the asymptomatic skeletally immature patient with a complete ACL tear. 2. If the patient remains asymptomatic, formal reconstruction can be delayed until skeletal maturity. 3. For the symptomatic patient a precise delineation of their physical development or skeletal age is important. 4. In patients who have reached Tanner IV secondary sexual development or a skeletal age of 13-14 (F/M), a traditional transphyseal reconstruction with hamstring autografts is appropriate. 5. In the skeletally immature patient who has significant skeletal development ahead of them, the judicious use of physeal sparing procedures is an option for the surgeon comfortable with these techniques. In this case the goal is temporization until formal transphyseal reconstruction can be performed after the peak of skeletal growth.

Adolescent↗
PubMed1999

Normalized and proportionalized cemented femoral stem survivorship at 15 years.

We reviewed the clinical and radiographic results of a series of 215 consecutive hip arthroplasties in which a normalized, proportionalized, cemented femoral component was implanted. This component design may encourage more efficient force transmission from prosthesis to cement to bone and lessen hoop stresses and resultant interface failure. A total of 127 hips in 103 patients with a follow-up of 13 to 17 years (average, 14.8 years) were available for evaluation, which included survivorship analysis. An aseptic failure loosening rate of 3.9% at 15 years for this stem favorably compares with other reported series of first-generation and second-generation stems at similar follow-up. Excluding the 8 stems placed in varus, of which 3 required revision (failure rate, 37.5%), the series has a failure rate of 1.6%.

Adult↗
PubMed1999

Matrix metalloproteinase inhibitors: applications in oncology.

Matrix metalloproteinases (MMP) are a group of zinc dependent enzymes which include the interstitial collagenases, stromelysins, gelatinases and membrane-type metalloproteinases. They are involved in the remodelling and turnover of the extracellular matrix proteins. They play a role in wound healing and the pathogenesis of arthritis. In malignancies they play a role in tumor invasion, metastasis and angiogenesis. A number of synthetic matrix metalloproteinase inhibitors (MMPIs) have been developed for clinical use. In preclinical tumor models they have shown promising activity in achieving inhibition of MMPs and reducing tumor growth and metastatic spread. Some have also shown additive or synergistic effects with cytotoxic agents. Phase I and II studies in human subjects have defined the main side effects of these agents as being musculoskeletal pains or arthralgias. As they are cytostatic agents rather than cytotoxic in activity conventional measurements of radiological response for assessment are not applicable in trials. Biological activity has been demonstrated in certain cancers by the effects on levels of tumor markers as surrogate markers of tumor response and also by a fibrotic stromal reaction seen in tumor tissue. Newer agents have been developed with selective inhibition of certain MMPs in an attempt to reduce the side effects. A number of phase III human clinical trials evaluating MMPs are being carried out at present but only one has been formally reported so far. This study suggested that marimastat had no survival advantage when compared to chemotherapy with gemcitabine in advanced pancreatic carcinoma. Current trials are assessing efficacy of MMPIs in maintenance of remission after other modalities of therapy or in combination with cytotoxic agents. MMPs have also been demonstrated to play an important role in the articular cartilage destruction seen in both rheumatoid arthritis and osteoarthritis. The use of MMPIs in both ex vivo and in vivo models have shown promising results and trials are in process to assess their potential role in the control of articular destruction. The true therapeutic role of MMPIs await the results of these randomized studies.

Animals↗
PubMed1996

Comparison of the behavioural effects of infusion of carbachol and acetylcholinesterase into the rat substantia nigra.

It has been postulated for many years that acetylcholinesterase (AChE) may play a nonclassical role in the substantia nigra, unrelated to its ability to hydrolyse acetylcholine. In this study the behavioural effects of unilateral infusion of AChE and a cholinergic agonist, carbachol, were compared. Carbachol induced ipsiversive circling over a very short time scale (minutes), whereas AChE induced contraversive circling, but over a longer time course-10 days. Both agents showed selectivity of response within the substantia nigra: acetylcholinesterase was only effective when infused into the most rostral region of the substantia nigra and its effects were limited to the pars compacta. In contrast, carbachol had effects in both the pars compacta and reticulata, with a graded sensitivity to carbachol in the rostral/caudal plane; infusions into rostral regions induced high rates of circling compared to more caudal areas, suggesting that the cholinergic input to the substantia nigra is not homogenous, but greater in rostral regions. This disparity between the effects of carbachol and AChE would, therefore, suggest that AChE is not exerting its long-term behavioural actions via a cholinergic mechanism, both in terms of time course of the response and the areas within the substantia nigra sensitive to these agents.

Acetylcholinesterase↗
PubMed1996

Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery.

PURPOSE: We investigated the outcome of nephron sparing surgery in patients with low grade and low stage (Robson stage II or less) renal cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the records of 185 patients treated with nephron sparing surgery and 209 matched for patient age and sex, and tumor stage and grade who were treated with radical nephrectomy. Kaplan-Meier survival curves were constructed for progression and survival end points. Multivariate analysis was performed to determine the tumor characteristics independently correlated with progression and cancer death. RESULTS: No significant difference was observed with respect to progression-free, crude or cancer specific survival between the nephron sparing surgery and radical nephrectomy groups. Less than 5% of the patients treated with conservative nephron sparing surgery had local recurrence. Tumor size was a strong independent predictor of outcome, whereas Robson stage was not. Patients treated with radical nephrectomy had a significant cancer specific and progression-free survival advantage when controlling for tumor diameter and grade. However, no difference was observed in patients with primary tumor diameters of 4 cm. or less. CONCLUSIONS: Robson staging is inaccurate in predicting tumor behavior. Patients with tumors larger than 4 cm. and a normal contralateral kidney may be best served by radical nephrectomy rather than elective nephron sparing surgery. However, nephron sparing surgery may result in an outcome similar to that of radical nephrectomy for low grade, low stage renal cell carcinomas of 4 cm. or smaller.

Carcinoma, Renal Cell↗
PubMed1995

Recombinant acetylcholinesterase has behavioural effects in the rat substantia nigra not attributable to its enzymatic activity.

An unexplained action of acetylcholinesterase (AChE) has previously been demonstrated on motor behaviour in the substantia nigra: a single infusion of the protein induced long-term circling behaviour, reflecting sustained increased activity of the nigro-striatal pathway. In this study, a highly purified form of AChE was infused and the long-term behavioural effects were still observed. In addition, recombinant human AChE produced a similar response, suggesting that AChE itself, and not a contaminant, was responsible for these behavioural actions. Butyrylcholinesterase, which also hydrolyses acetylcholine, was without effect. Hence AChE is not exerting these actions by potentiating the neurotransmitter acetylcholine, but via some cholinergic-independent mechanism.

Acetylcholinesterase↗
PubMed1995

Influence of DNA ploidy and adjuvant treatment on progression and survival in patients with pathologic stage T3 (PT3) prostate cancer after radical retropubic prostatectomy.

OBJECTIVES: To determine whether adjuvant treatment (AT: hormonal or radiation) affects outcome in pathologic Stage T3 (pT3) prostate cancer when analyzed according to DNA ploidy. METHODS: The predictive value of nuclear DNA ploidy and AT on clinical and prostate-specific antigen (PSA) progression and on overall and cause-specific survival after radical retropubic prostatectomy was assessed in 894 patients with pT3 prostate cancer. RESULTS: Mean follow-up was 6.7 years (range, 0.3 to 20). Mean age was 66 years (range, 39 to 79). Six hundred sixty patients (74%) had no immediate AT, 131 (15%) had early adjuvant radiotherapy (ART), and 103 (12%) had early adjuvant orchiectomy (AHT). DNA diploid tumors were found in 445 patients (52%), tetraploid tumors in 346 (41%), and aneuploid tumors in 59 (7%). DNA ploidy was a significant (P < 0.05) prognostic indicator for clinical systemic progression-free survival. With PSA progression (more than 0.2 ng/mL) as an endpoint, ploidy was an even more powerful predictor for outcome (P = 0.004). Use of early AHT or ART was associated with decreased overall clinical progression for diploid and nondiploid tumors (P < 0.001 and P < 0.001, respectively). With respect to PSA progression, ART and AHT were equally effective and superior to no AT only in patients with diploid tumors. However, in patients with nondiploid tumors, only AHT appeared to have improved PSA progression-free survival (P < 0.001) over ART or no AT, which are similar in outcome. CONCLUSIONS: In the present nonrandomized study, AHT was as effective as ART for all endpoints except for PSA more than 0.2 ng/mL progression, for which it appeared to be superior to ART for patients with nondiploid tumors.

Adult↗
PubMed1992

Non-cholinergic action of exogenous acetylcholinesterase in the rat substantia nigra. I. Differential effects on motor behaviour.

In the substantia nigra a non-cholinergic action of acetylcholinesterase has been demonstrated on motor behaviour. At the cellular level, electrophysiological studies have shown not only excitatory actions of AChE, but also inhibitory effects in response to larger amounts of the protein. In this study the possible dose-dependent effects of AChE were therefore explored in relation to circling behaviour. Both 'ipsiversive' turning (towards side of infusion and indicative of net decreased activity in the nigrostriatal pathway) and 'contraversive' turning (away from side of infusion and indicative of net increased activity) was observed for at least 2 weeks following a single unilateral AChE infusion. Ipsiversive turning occurred in 15-20% of animals in each group irrespective of dose. However, the actual number of animals exhibiting contraversive turning increased with increasing dose, whilst those not responding decreased. The most critical factor for direction of response appeared to be related not to dose, but cannula placement; infusion of AChE into more posterior regions of the substantia nigra evoked contraversive circling, whereas there appeared to be a discrete site in the anterior nigra in which AChE induced ipsiversive turning. This study thus suggests that subpopulations of nigrostriatal neurons show differential responsiveness to AChE.

Acetylcholinesterase↗
PubMed1992

Non-cholinergic action of exogenous acetylcholinesterase in the rat substantia nigra. II. Long-term interactions with dopamine metabolism.

Within the substantia nigra acetylcholinesterase (AChE) has a novel non-cholinergic action that is functionally manifest as chronic circling behaviour in rats. The aim of this study was to explore the possible biochemical mechanisms that could underlie the long-term behavioural effects of this protein, infused unilaterally into one substantia nigra. A single treatment of acetylcholinesterase induced modest but consistent circling behaviour in the presence of a systemic amphetamine challenge for the maximum time tested, up to 50 days: comparable infusions of saline were without effect. When animals received a challenge of the direct dopamine agonist apomorphine, no AChE-induced circling was observed: this result suggested that the phenomenon did not entail a down-regulation of striatal dopamine receptors. On the other hand, a challenge of the dopamine uptake inhibitor nomifensine resulted in AChE-induced circling that was indistinguishable from that seen in the presence of amphetamine: hence the circling behaviour seen could be attributable to an AChE-induced increase in availability of extracellular dopamine. In animals where AChE caused contraversive rotation, indicative of an enhanced activity in the nigrostriatal pathway, there was a significant elevation in the dopamine content of the striatum on the treated side. It is concluded that AChE can chronically enhance the release of dopamine from the nigrostriatal pathway such that motor behaviour is correspondingly modified, but to an extent sufficiently modest to avoid compensatory synaptic reversal mechanisms.

Acetylcholinesterase↗
PubMed1991

Actions of insecticides on the insect GABA receptor complex.

The actions of insecticides on the insect gamma-aminobutyric acid (GABA) receptor were investigated using [35S]t-butylbicyclophosphorothionate [( 35S]TBPS) binding and voltage-clamp techniques. Specific binding of [35S]TBPS to a membrane homogenate derived from the brain of Locusta migratoria locusts is characterised by a Kd value of 79.3 +/- 2.9 nM and a Bmax value of 1770 +/- 40 fmol/mg protein. [35S]TBPS binding is inhibited by mM concentrations of barbiturates and benzodiazepines. In contrast dieldrin, ivermectin, lindane, picrotoxin and TBPS are inhibitors of [35S]TBPS binding at the nanomolar range. Bicuculline, baclofen and pyrethroid insecticides have no effect on [35S]TBPS binding. These results are similar to those obtained in electrophysiological studies of the current elicited by GABA in both Locusta and Periplaneta americana central neurones. Noise analysis of the effects of lindane, TBPS, dieldrin and picrotoxin on the cockroach GABA responses reveals that these compounds decrease the variance of the GABA-induced current but have no effect on its mean open time. All these compounds, with the exception of dieldrin, significantly decrease the conductance of GABA-evoked single current.

Animals↗
PubMed1988

The influence of steroid hormones on competing sexual and ingestive behavior in the male rat.

Water replete rats allowed restricted access to a sweet nonnutritive solution (0.2% Acesulfame-K) spend about one third of their time drinking it. This ingestive response is markedly inhibited if the male rat is simultaneously presented with an estrous female, but not an anestrous female or another male, despite the fact that there is sufficient time for both sexual and ingestive behaviors to occur. Castration and the subsequent decline in sexual behavior is accompanied by an increase in Acesulfame ingestion in the presence of a receptive female. Treatment with testosterone reverses both these effects. Similarly treatment of castrate males with DHT and estradiol (the active metabolites of testosterone) maintains both full sexual behavior and suppression of the ingestive response. However, the steroid requirements for sexual activity do not correspond completely with those for the sexually-induced suppression of ingestive behavior. Treatment of castrate males with estradiol alone maintains mounting behavior (but no intromissions or ejaculations) but does not suppress ingestive behavior in the presence of a receptive female--indeed under these suboptimal hormone conditions sexual behavior appears to be reduced in the presence of Acesulfame. Steroid hormones, therefore, have at least two effects upon sexual behavior. They enable certain aspects of sexual behavior such as intromissions and ejaculations, and also alter the animal's priority of response to two competing (ingestive and sexual) stimuli.

Animals↗
PubMed1985

Antiepileptic and antiamnesic effect of carbamazepine in experimental limbic epilepsy.

Carbamazepine (20 mg/kg, 40 mg/kg or 60 mg/kg) given three times a day, has been demonstrated to have a significant anti-epileptic effect in rats with chronic limbic epilepsy induced by injecting tetanus toxin bilaterally into their hippocampi. This effect involved a reduction in the maximum number of fits occurring on one day, and with the highest dose, a significant reduction in the total number of fits. In a pilot experiment in which continuous EEG records were obtained throughout the syndrome, it appeared that the effect of carbamazepine was to reduce the proportion of EEG seizure discharges which lead to overt motor fits. With the higher drug dose plasma levels of carbamazepine were maintained around 2 micrograms/ml. This experimental epilepsy produces enduring deficits in the rats' memories for a light-discrimination task in a Y-maze learned before induction of epilepsy (8 weeks after initial learning). If the rats are dosed with carbamazepine during their epilepsy this memory deficit is abolished.

Amnesia↗