PubMed Health⌕ Search

Biomedical subjects

T A Cook

Publications and source records attributed to T A Cook.

At least 19 recordsLinked to original sources
PubMed2007

Optical adjuncts for enhanced colonoscopic diagnosis.

BACKGROUND: Optical techniques using previously unexploited properties of light interaction with tissue may be valuable in the detection, diagnosis and staging of colorectal neoplasia. METHODS: A Medline search (1990 to present) was conducted on optical diagnostics in the detection of colorectal neoplasia. The reference list of each identified article was reviewed for further relevant papers. RESULTS AND CONCLUSION: Chromoendoscopy is the only optical adjunct to colonoscopy that has been tested in large randomized clinical trials. It improves the detection of small and flat colorectal adenomas, and of neoplasia in chronic ulcerative colitis and hereditary non-polyposis colorectal cancer. All other techniques are the subject of ongoing research and the practicality of population screening with any of the methods has yet to be established. Optical techniques may, however, permit immediate clinical diagnosis, removing the need for histological analysis. They may also improve the diagnosis of early colonic neoplasia.

Colonoscopy↗
PubMed2005

Bowel function following insertion of self-expanding metallic stents for palliation of colorectal cancer.

OBJECTIVE: Self-expanding metallic stents (SEMS) are an important addition to the treatment of large bowel obstruction. The aim of this study was firstly to assess bowel function following SEMS placement and secondly to identify any potential factors which might aid in the prediction of technical failure of stent insertion. METHODS: A review of all patients undergoing attempted SEMS placement for palliation of malignant left-sided colorectal obstruction over a four-year period (1st May 2000-30th April 2004) was performed. RESULTS: Twenty-one patients (12 male) with a median age of 76 years (range 48-92 years) were included, 11 with metastatic disease and 10 severe comorbidity. SEMS insertion was technically successful in 16 (76%) of 21 cases. Contrast successfully passed through the obstructing lesion in all 16 cases where SEMS placement was technically successful. It only passed through 1 of 5 cases where stenting was not possible (P = 0.0008, Fisher's Exact test). Complications included colonic perforation (1 case), stent migration (1 case) and tumour ingrowth requiring a second stent (1 case). Median survival after SEMS was 12 months (range 1-30 months), and 9 patients died during follow-up. Median bowel frequency following SEMS was 3.5 times per day (range 1-7). Eight patients always passed a liquid stool, 3 others regularly required laxatives and one further patient with poor function after stenting requested a defunctioning stoma. CONCLUSION: Failure of contrast to pass through the obstructing lesion may predict those cases where stenting will not be technically possible. Median survival following SEMS insertion is encouraging in this series, but bowel function is often poor. Expected bowel function should be discussed fully when consenting patients for a SEMS, particularly those with metastatic disease who are otherwise fit for resectional surgery.

Aged↗
PubMed2001

mDia mediates Rho-regulated formation and orientation of stable microtubules.

Rho-GTPase stabilizes microtubules that are oriented towards the leading edge in serum-starved 3T3 fibroblasts through an unknown mechanism. We used a Rho-effector domain screen to identify mDia as a downstream Rho effector involved in microtubule stabilization. Constitutively active mDia or activation of endogenous mDia with the mDia-autoinhibitory domain stimulated the formation of stable microtubules that were capped and oriented towards the wound edge. mDia co-localized with stable microtubules when overexpressed and associated with microtubules in vitro. Rho kinase was not necessary for the formation of stable microtubules. Our results show that mDia is sufficient to generate and orient stable microtubules, and indicate that Dia-related formins are part of a conserved pathway that regulates the dynamics of microtubule ends.

3T3 Cells↗
PubMed2001

The pharmacology of the internal anal sphincter and new treatments of ano-rectal disorders.

Surgical options for faecal incontinence in the presence of intact sphincters are limited. Furthermore, in patients with fissures, lateral sphincterotomy reduces anal sphincter hypertonia but there has been concern about complications. A greater understanding of the basic pharmacology of the internal anal sphincter has led to the development of novel treatments for both these disorders. A Medline review was undertaken for internal anal sphincter pharmacology, anal fissures and faecal incontinence. This review is based on these articles and those found by further cross-referencing. Nitric oxide released from non-adrenergic non-cholinergic nerves is the main inhibitory agent in the internal anal sphincter. Relaxations are also mediated through beta-adrenoceptors and muscarinic receptors. Stimulation of alpha-receptors results in contraction. Calcium and its entry through L-type calcium channels is important for the maintenance of tone. Nitric oxide donors produce reductions in resting anal tone and heal fissures but are associated with side-effects. Muscarinic agents and calcium channel antagonists show promise as low side-effect alternatives. Botulinum toxin appears more efficacious than other agents in healing fissures. To date, alpha-receptor agonists have been disappointing at improving incontinence. Further understanding of the pharmacology of the internal anal sphincter may permit the development of new agents to selectively target the tissue with greater efficacy and fewer side-effects.

Adrenergic alpha-Agonists↗
PubMed2001

Emerging perceptions of facial plastic surgery among medical students.

OBJECTIVE: The purpose of this study was to examine the perceptions of medical students regarding facial aesthetic surgery and those specialists most likely to perform aesthetic or reconstructive facial surgery. METHODS: A survey was designed based on a review of the literature to assess the desirable characteristics and the perceived role of the facial plastic and reconstructive surgeon (FPRS). The surveys were distributed to 2 populations: medical students from 4 medical schools and members of the general public. RESULTS: A total of 339 surveys were collected, 217 from medical students and 122 from the general public. Medical students and the public had similar responses. The results demonstrated that respondents preferred a male plastic surgeon from the ages of 41 to 50 years old and would look to their family doctor for a recommendation. Facial aesthetic and reconstructive surgery was considered the domain of maxillofacial and general plastic surgeons, not the FPRS. CONCLUSION: Integration of the FPRS into the medical school curriculum may help to improve the perceived role of the specialty within the medical community. It is important for the specialty to communicate to aspiring physicians the dedicated training of an otolaryngologist specializing in FPRS.

Adult↗
PubMed2000

Binding of the delta subunit to rod phosphodiesterase catalytic subunits requires methylated, prenylated C-termini of the catalytic subunits.

PDE6 (type 6 phosphodiesterase) from rod outer segments consists of two types of catalytic subunits, alpha and beta; two inhibitory gamma subunits; and one or more delta subunits found only on the soluble form of the enzyme. About 70% of the phosphodiesterase activity found in rod outer segments is membrane-bound, and is thought to be anchored to the membrane through C-terminal prenyl groups. The recombinant delta subunit has been shown to solubilize the membrane-bound form of the enzyme. This paper describes the site and mechanism of this interaction in more detail. In isolated rod outer segments, the delta subunit was found exclusively in the soluble fraction, and about 30% of it did not coimmunoprecipitate with the catalytic subunits. The delta subunit that was bound to the catalytic subunits dissociated slowly, with a half-life of about 3.5 h. To determine whether the site of this strong binding was the C-termini of the phosphodiesterase catalytic subunits, peptides corresponding to the C-terminal ends of the alpha and beta subunits were synthesized. Micromolar concentrations of these peptides blocked the phosphodiesterase/delta subunit interaction. Interestingly, this blockade only occurred if the peptides were both prenylated and methylated. These results suggested that a major site of interaction of the delta subunit is the methylated, prenylated C-terminus of the phosphodiesterase catalytic subunits. To determine whether the catalytic subunits of the full-length enzyme are methylated in situ when bound to the delta subunit, we labeled rod outer segments with a tritiated methyl donor. Soluble phosphodiesterase from these rod outer segments was more highly methylated (4.5 +/- 0.3-fold) than the membrane-bound phosphodiesterase, suggesting that the delta subunit bound preferentially to the methylated enzyme in the outer segment. Together these results suggest that the delta subunit/phosphodiesterase catalytic subunit interaction may be regulated by the C-terminal methylation of the catalytic subunits.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

The delta subunit of type 6 phosphodiesterase reduces light-induced cGMP hydrolysis in rod outer segments.

The delta subunit of the rod photoreceptor PDE has previously been shown to copurify with the soluble form of the enzyme and to solubilize the membrane-bound form (). To determine the physiological effect of the delta subunit on the light response of bovine rod outer segments, we measured the real time accumulation of the products of cGMP hydrolysis in a preparation of permeablized rod outer segments. The addition of delta subunit GST fusion protein (delta-GST) to this preparation caused a reduction in the maximal rate of cGMP hydrolysis in response to light. The maximal reduction of the light response was about 80%, and the half-maximal effect occurred at 385 nm delta subunit. Several experiments suggest that this effect was not due to the effects of delta-GST on transducin or rhodopsin kinase. Immunoblots demonstrated that exogenous delta-GST solubilized the majority of the PDE in ROS but did not affect the solubility of transducin. Therefore, changes in the solubility of transducin cannot account for the effects of delta-GST in the pH assay. The reduction in cGMP hydrolysis was independent of ATP, which indicates that it was not due to effects of delta-GST on rhodopsin kinase. In addition to the effect on cGMP hydrolysis, the delta-GST fusion protein slowed the turn-off of the system. This is probably due, at least in part, to an observed reduction in the GTPase rate of transducin in the presence of delta-GST. These results demonstrate that delta-GST can modify the activity of the phototransduction cascade in preparations of broken rod outer segments, probably due to a functional uncoupling of the transducin to PDE step of the signal transduction cascade and suggest that the delta subunit may play a similar role in the intact outer segment.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

Percutaneous endoscopic gastrostomy at the time of tumour resection in advanced oral cancer.

The role of percutaneous endoscopic gastrostomy (PEG) in patients undergoing resection of head and neck malignancy is well established. The procedure may be performed pre- or post-operatively with intravenous sedation or alternatively under general anaesthesia at the time of tumour resection. There are concerns as to the safety of PEG, particularly when performed under intravenous sedation. Elderly patients with poor general health and those with airway compromise may be at significant risk. We believe that patients with advanced oral malignancy often fall into such groups and, therefore, we routinely perform PEG at the time of resection. The aim of this study was to determine the potential risk factors for PEG insertion in patients with advanced oral malignancy and present our experience with insertion at the time of resection. A retrospective study was undertaken of the risk factors for PEG insertion in 72 consecutive patients with stage IV oral cancer treated between April 1993 and March 2000. Age, sex, tumour site, past medical history, American Society of Anaesthesiologists (ASA) and laryngoscopy grade, as an assessment of potential airway compromise, were recorded. There were 72 patients, 40 males and 32 females, with a mean age of 63 years (27-90). Eighteen patients (25%) scored 3 or 4 on the ASA scores of physical status. Laryngoscopy grades were recorded in 65 patients; of these, 18 (25%) had reduced visualisation of the larynx and in two patients not even the epiglottis could be seen. It is concluded that patients with advanced oral cancer have significant risk factors for PEG placement. However, PEG can be safely performed at the time of ablative surgery and has the advantage of avoiding an additional operative event for the patient.

Adult↗
PubMed2000

Abnormal contractile properties of rectal smooth muscle in chronic ulcerative colitis.

BACKGROUND: Patients with ulcerative colitis have abnormal rectal motility. AIM: To compare the contractile properties of rectal smooth muscle from patients with ulcerative colitis and controls. METHODS: Rectal smooth muscle strips from patients undergoing resection for ulcerative colitis or cancer (control) were mounted in an organ bath. The effects of carbachol (receptor-mediated) and potassium (causes membrane depolarization) were studied. Acetylcholinesterase histochemistry was performed and nerve counts compared. RESULTS: Ulcerative colitis (n=41) and control (n=34) strips contracted in response to potassium and carbachol. Mean (S.E. M.) maximum response to potassium in the control and ulcerative colitis groups was 1.07 (0.06) g/mg and 1.02 (0.09) g/mg tissue, respectively (P=N.S.). EC50s (concentrations required to give 50% of maximal response) were 75 (1) mM and 73 (1) mM, respectively (P=N.S. ). Although maximum responses to carbachol were similar, 2.12 (0.12) g/mg and 1.95 (0.12) g/mg tissue (P=N.S.), ulcerative colitis strips exhibited an increased sensitivity to carbachol, EC50s: 5.05 x 10-6 (0.55 x 10-6) M vs. 8.36 x 10-6 (0.88 x 10-6) M, P=0.002). There was no significant difference in nerve counts between the tissues, as assessed by staining for acetylcholinesterase. CONCLUSIONS: Ulcerative colitis tissue has an increased sensitivity to carbachol and this is not due to denervation; it may result from increased calcium release from intracellular stores since contraction due to membrane depolarization is not altered. Modulation of this pathway could potentially be used to alter rectal motility in patients with ulcerative colitis.

Acetylcholinesterase↗
PubMed1999

cGMP binding to noncatalytic sites on mammalian rod photoreceptor phosphodiesterase is regulated by binding of its gamma and delta subunits.

The binding of cGMP to the noncatalytic sites on two isoforms of the phosphodiesterase (PDE) from mammalian rod outer segments has been characterized to evaluate their role in regulating PDE during phototransduction. Nonactivated, membrane-associated PDE (PDE-M, alpha beta gamma2) has one exchangeable site for cGMP binding; endogenous cGMP remains nonexchangeable at the second site. Non-activated, soluble PDE (PDE-S, alpha beta gamma2 delta) can release and bind cGMP at both noncatalytic sites; the delta subunit is likely responsible for this difference in cGMP exchange rates. Removal of the delta and/or gamma subunits yields a catalytic alphabeta dimer with identical catalytic and binding properties for both PDE-M and PDE-S as follows: high affinity cGMP binding is abolished at one site (KD >1 microM); cGMP binding affinity at the second site (KD approximately 60 nM) is reduced 3-4-fold compared with the nonactivated enzyme; the kinetics of cGMP exchange to activated PDE-M and PDE-S are accelerated to similar extents. The properties of nonactivated PDE can be restored upon addition of gamma subunit. Occupancy of the noncatalytic sites by cGMP may modulate the interaction of the gamma subunit with the alphabeta dimer and thereby regulate cytoplasmic cGMP concentration and the lifetime of activated PDE during visual transduction in photoreceptor cells.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1999

Effects of nifedipine on anorectal smooth muscle in vitro.

INTRODUCTION: Glyceryl trinitrate reduces anal resting pressure and aids the healing of anal fissures. However, some patients develop tachyphylaxis and the fissure fails to heal, suggesting that other agents are needed. This study assesses the effects of nifedipine (a calcium channel antagonist) in modulating resting tone and agonist-induced contractions in human internal anal sphincter (IAS) and rectal circular muscle. METHODS: Smooth muscle strips from the IAS and rectal circular muscle from ten patients undergoing surgical resection were mounted for isometric tension recording in a superfusion organ bath. The effects of noradrenaline and carbachol were assessed in the presence of various perfusates. RESULTS: LAS strips developed tone and spontaneous activity. Noradrenaline produced dose-dependent contractions. In calcium-free Krebs solution, tone and activity were abolished and no contractions were elicited in response to noradrenaline. Nifedipine also abolished tone and spontaneous activity, but contractions to noradrenaline were only slightly attenuated. In contrast, rectal smooth muscle strips developed spontaneous activity but no resting tone and contracted in response to carbachol. In calcium-free Krebs solution, the spontaneous activity and carbachol contractions were abolished. Addition of nifedipine to the perfusate abolished spontaneous activity and greatly reduced contractions. DISCUSSION: These data suggest that spontaneous activity and resting tone are dependent on extracellular calcium and flux across the cells. Agonist-induced contraction in the IAS is attributable mainly to the release of calcium from intracellular stores, whereas rectal circular smooth muscle depends principally on extracellular calcium entering the cell for contraction. The attenuation of contractions in both tissues and the abolition of resting tone in the IAS suggest that nifedipine may be useful in the management of patients with anorectal disorders.

Adult↗
PubMed1999

Microtubules and signal transduction.

Although molecular components of signal transduction pathways are rapidly being identified, how elements of these pathways are positioned spatially and how signals traverse the intracellular environment from the cell surface to the nucleus or to other cytoplasmic targets are not well understood. The discovery of signaling molecules that interact with microtubules (MTs), as well as the multiple effects on signaling pathways of drugs that destabilize or hyperstabilize MTs, indicate that MTs are likely to be critical to the spatial organization of signal transduction. MTs themselves are also affected by signaling pathways and this may contribute to the transmission of signals to downstream targets.

Animals↗
PubMed1999

Differences in contractile properties of anorectal smooth muscle and the effects of calcium channel blockade.

BACKGROUND: Pharmacological manipulation of the anal sphincter is hampered by a lack of specificity. This study aimed to determine differences in the role of intracellular and extracellular calcium in the development of tone and agonist-induced contractions between internal anal sphincter (IAS) and rectal circular muscle which might allow targeted manipulation. METHODS: Smooth muscle strips from the IAS and rectal circular muscle of 24 Large White pigs were mounted for isometric tension recording in a superfusion organ bath in the presence of different perfusates. RESULTS: IAS developed tone and spontaneous activity that were abolished by nifedipine, which also reduced contractions to noradrenaline to 72 per cent of control values. Rectal smooth muscle developed spontaneous activity but no tone. Nifedipine abolished the activity and reduced contractions to carbachol to 17 per cent of control. Contractile activity was abolished in both tissues in calcium-free solution. Transient exposure to a high calcium concentration reloaded the stores, and the ability of agonists to release stored calcium was tested after 3 min in calcium-free solution. In IAS, noradrenaline contraction was 76 per cent of control and in rectal circular muscle carbachol contraction was 57 per cent of control. Store loading was prevented by nifedipine in rectal smooth muscle but not IAS. Cyclopiazonic acid reduced store filling in both tissues. CONCLUSION: Agonist-induced contraction of IAS is largely due to release of stored calcium and L-type calcium channels are not needed for store filling. Rectal circular smooth muscle depends more on extracellular calcium and uses L-type calcium channels for agonist-induced contraction and store filling. These differences suggest that targeted manipulation may be possible in patients with anorectal disorders.

Adrenergic alpha-Antagonists↗
PubMed1999

Oral nifedipine reduces resting anal pressure and heals chronic anal fissure.

BACKGROUND: Topical preparations have been used in the treatment of anal fissure. However, they are not universally successful and there is confusion over the site and dose of application. This study assessed the effectiveness of oral nifedipine in reducing resting anal pressure and on fissure healing. METHODS: Anal manometry was performed on eight healthy volunteers and 15 patients with chronic anal fissure before and after oral administration of nifedipine 20 mg. Nifedipine was taken twice daily. Fissure healing was assessed over an 8-week period and pain scores were monitored. RESULTS: Oral nifedipine produced an initial reduction in maximum resting anal pressure (MRP) of 35 per cent (P < 0.001) and of 28 per cent after 5 days (P < 0.001) in healthy volunteers. A reduction in MRP of 36 per cent (P < 0.001) was observed in patients with fissure. Pain scores were significantly reduced during the treatment period. Healing was complete in nine patients after 8 weeks and a further three were asymptomatic. Ten patients experience flushing and four had mild headaches. There were no episodes of postural hypotension or incontinence. CONCLUSION: Oral nifedipine reduces resting anal pressure. It is well tolerated and offers an alternative treatment for chronic anal fissure.

Administration, Oral↗